1601. Nuclear magnetic resonance metabolic fingerprint of bevacizumab in mutant IDH1 glioma cellsTanja Mesti, Nadia Bouchemal, Claire Banissi, Mohamed N. Triba, Carole Marbeuf-Gueye, Maja Čemažar, Laurence Le Moyec, Antoine F. Carpentier, Philippe Savarin, Janja Ocvirk, 2018, original scientific article Abstract: Malignant gliomas are rapidly growing tumours that extensively invade the brain and have bad prognosis. Our study was performed to assess the metabolic effects of bevacizumab on the glioma cells carrying the IDH1 mutation, a mutation, associated with better prognosis and treatment outcome. Bevacizumab is known to inhibit tumour growth by neutralizing the biological activity of vascular endothelial growth factor (VEGF). However, the direct effects of bevacizumab on tumour cells metabolism remain poorly known. Materials and methods The immunoassay and MTT assay were used to assess the concentration of secreted VEGF and cell viability after bevacizumab exposure. Metabolomic studies on cells were performed using high resolution magic angle spinning spectroscopy (HRMAS). Results mIDH1-U87 cells secreted VEGF (13 ng/mL). Regardless, bevacizumab had no cytotoxic effect, even after a 72h exposure and with doses as high as 1 mg/mL. Yet, HRMAS analysis showed a significant effect of bevacizumab (0.1 mg/mL) on the metabolic phenotype of mIDH1-U87 cells with elevation of 2-hydroxyglutarate and changes in glutamine group metabolites (alanine, glutamate, glycine) and lipids (polyunsaturated fatty acids [PUFA], glycerophosphocholine, and phosphocholine). Conclusions In mIDH1-U87 cells, changes in glutamine group metabolites and lipids were identified as metabolic markers of bevacizumab treatment. These data support the possibility of a functional tricarboxylic acid cycle that runs in reductive manner, as a probable mechanism of action of bevacizumab in IDH1 mutated gliomas and propose a new target pathway for effective treatment of malignant gliomas.
Keywords: symptomatic pseudoprogression, atypical response, immunotherapy, lung cancer, idh1 mutation, malignant glioma, bevacizumab, metabolic fingerprint
Published in DiRROS: 11.06.2024; Views: 289; Downloads: 128
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1602. Ultrasonographic changes in the liver tumors as indicators of adequate tumor coverage with electric field for effective electrochemotherapyNina Boc, Ibrahim Edhemović, Bor Kos, Maja Marolt-Mušič, Erik Brecelj, Blaž Trotovšek, Maša Omerzel, Mihajlo Djokić, Damijan Miklavčič, Maja Čemažar, Gregor Serša, 2018, original scientific article Abstract: The aim of the study was to characterize ultrasonographic (US) findings during and after electrochemotherapy of liver tumors to determine the actual ablation zone and to verify the coverage of the treated tumor with a sufficiently strong electric field for effective electrochemotherapy. Patients and methods. US findings from two representative patients that describe immediate and delayed tumor changes after electrochemotherapy of colorectal liver metastases are presented. Results. The US findings were interrelated with magnetic resonance imaging (MRI). Electrochemotherapy-treated tumors were exposed to electric pulses based on computational treatment planning. The US findings indicate immediate appearance of hyperechogenic microbubbles along the electrode tracks. Within minutes, the tumors became evenly hyperechogenic, and simultaneously, an oedematous rim was formed presenting as a hypoechogenic formation which persisted for several hours after treatment. The US findings overlapped with computed electric field distribution in the treated tissue, indicating adequate coverage of tumors with sufficiently strong electric field, which may predict an effective treatment outcome. Conclusions. US provides a tool for assessment of appropriate electrode insertion for intraoperative electrochemotherapy of liver tumors and assessment of the appropriate coverage of a tumor with a sufficiently strong electric field and can serve as predictor of the response of tumors.
Keywords: elctrochemotherapy, ultrasound, treatment plan, liver
Published in DiRROS: 11.06.2024; Views: 347; Downloads: 121
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1603. Primary debulking surgery versus primary neoadjuvant chemotherapy for high grade advanced stage ovarian cancer : comparison of survivalsBorut Kobal, Marco Noventa, Branko Cvjetičanin, Matija Barbič, Leon Meglič, Maruša Herzog, Giulia Bordi, Amerigo Vitagliano, Carlo Saccardi, Erik Škof, 2018, original scientific article Abstract: The aim of the study was to analyze the overall survival (OS) and progression free survival (PFS) of patients with high grade and advanced stage epithelial ovarian cancer (EOC) with at least 60 months of follow-up treated in a single gynecologic oncology institute. We compared primary debulking surgery (PDS) versus neoadjuvant chemotherapy plus interval debulking surgery (NACT + IDS) stratifying data based on residual disease with the intent to identify the rationale for therapeutic option decision and the role of laparoscopic evaluation of resectability for that intention. Patients and methods. This is observational retrospective study on consecutive patients with diagnosis of high grade and International Federation of Gynecology and Obstetrics (FIGO) stage III/IV EOC referred to our center between January 2008 and May 2012. We selected only patients with a follow-up of at least 60 months. Primary endpoint was to compare PDS versus NACT + IDS in term of progression free survival (PFS) and overall survival (OS). Secondary endpoints were PFS and OS stratifying data according to residual disease after surgery in patients receiving PDS versus NACT + IDS. Finally, through Cox hazards models, we tested the prognostic value of different variables (patient age at diagnosis, residual disease after debulking, American Society of Anesthesiologists (ASA) stage, number of adjuvantchemotherapy cycles) for predicting OS. Results. A total number of 157 patients were included in data analysis. Comparing PDS arm (108 patients) and NACT + IDS arm (49 patients) we found no significant differences in term of OS (41.3 versus 34.5 months, respectively) and PFS (17.3 versus 18.3 months, respectively). According to residual disease we found no significant differences in term of OS between NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0 or residual disease = 1, as well as no significant differences in PFS were found comparing NACT + IDS patients with residual disease = 0 and PDS patients with residual disease = 0; contrarily, median PFS resulted significantly lower in PDS patients receiving optimal debulking (residual disease = 1) in comparison to NACT + IDS patients receiving complete debulking (residual disease = 0). PDS arm was affected by a significant higher rate of severe post-operative complications (grade 3 and 4). Diagnostic laparoscopy before surgery was significantly associated with complete debulking. Conclusions. We confirm previous findings concerning the non-superiority of NACT + IDS compared to PDS for the treatment of EOC, even if NACT + IDS treatment was associated with significant lower rate of post-operative complications. On the other hand, selecting patients for NACT + IDS, based on laparoscopic evaluation of resectabilty prolongs the PFS and does not worse the OS compared to the patients not completely debulked with PDS.
Keywords: epithelial ovarian cancer, advanced stage, primary debulking surgery, interval debulking surgery
Published in DiRROS: 11.06.2024; Views: 368; Downloads: 175
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1604. Induction chemotherapy, chemoradiotherapy and consolidation chemotherapy in preoperative treatment of rectal cancer : long-term results of phase II OIGIT-01 TrialDanijela Golo, Jasna But-Hadžić, Franc Anderluh, Erik Brecelj, Ibrahim Edhemović, Ana Jeromen, Mirko Omejc, Irena Oblak, Ajra Šečerov Ermenc, Vaneja Velenik, 2018, original scientific article Abstract: The purpose of the study was to improve treatment efficacy for locally advanced rectal cancer (LARC) by shifting half of adjuvant chemotherapy preoperatively to one induction and two consolidation cycles. Patients and methods Between October 2011 and April 2013, 66 patients with LARC were treated with one induction chemotherapy cycle followed by chemoradiotherapy (CRT), two consolidation cycles, surgery and three adjuvant capecitabine cycles. Radiation doses were 50.4 Gy for T2-3 and 54 Gy for T4 tumours in 1.8 Gy daily fraction. The doses of concomitant and neo/adjuvant capecitabine were 825 mg/m2/12h and 1250mg/m2/12h, respectively. The primary endpoint was pathologic complete response (pCR). Results Forty-three (65.1%) patients were treated according to protocol. The compliance rates for induction, consolidation, and adjuvant chemotherapy were 98.5%, 93.8% and 87.3%, respectively. CRT was completed by 65/66 patients, with G % 3 non-hematologic toxicity at 13.6%. The rate of pCR (17.5%) was not increased, but N and the total-down staging rates were 77.7% and 79.3%, respectively. In a median follow-up of 55 months, we recorded one local relapse (LR) (1.6%). The 5-year disease-free survival (DFS) and overall survival (OS) rates were 64.0% (95% CI 63.89%64.11) and 69.5% (95% CI 69.39%69.61), respectively. Conclusions In LARC preoperative treatment intensification with capecitabine before and after radiotherapy is well tolerated, with a high compliance rate and acceptable toxicity. Though it does not improve the local effect, it achieves a high LR rate, DFS, and OS.
Keywords: rectal cancer, neoadjuvant chemotherapy, preoperative chemoradiotherapy
Published in DiRROS: 11.06.2024; Views: 350; Downloads: 175
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1606. Immune RECIST criteria and symptomatic pseudoprogression in non-small cell lung cancer patients treated with immunotherapyMartina Vrankar, Mojca Unk, 2018, review article Abstract: Uncommon responses during immunotherapy is a new challenging issue in oncology practice. Recently, new criteria for evaluation of response to immunotherapy immune response evaluation criteria solid tumors (iRECIST) were accepted. According to iRECIST, worsening of performance status (PS) accompanied to pseudoprogression reflects most probably the true progression of the malignant disease. Methods. A systematic review of the literature was made by using several electronic database with the following search criteria: symptomatic pseudoprogression, atypical response, immunotherapy and lung cancer. Results. In the literature, we identified five reports of seven patients treated with immunotherapy that met the inclusion criteria. We also report our experience of patient with pseudoprogression and almost complete response after one dose of immunotherapy. Conclusions. As seen from our review, iRECIST criteria might be insufficient in distinguishing true progression from pseudoprogression in some patients with advanced NSCLC treated with immunotherapy. More precise assessment methods are urgently needed.
Keywords: symptomatic pseudoprogression, atypical response, immunotherapy, lung cancer
Published in DiRROS: 11.06.2024; Views: 298; Downloads: 102
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1607. Evaluation of two-dimensional dose distributions for pre-treatment patient-specific IMRT dosimetryĐeni Smilović Radojčić, David Rajlić, Božidar Casar, Manda Švabić Kolacio, Nevena Obajdin, Dario Faj, Slaven Jurković, 2018, original scientific article Abstract: The accuracy of dose calculation is crucial for success of the radiotherapy treatment. One of the methods that represent the current standard for patient-specific dosimetry is the evaluation of dose distributions measured with an ionization chamber array inside a homogeneous phantom using gamma method. Nevertheless, this method does not replicate the realistic conditions present when a patient is undergoing therapy. Therefore, to more accurately evaluate the treatment planning system (TPS) capabilities, gamma passing rates were examined for beams of different complexity passing through inhomogeneous phantoms. Materials and methods The research was performed using Siemens Oncor Expression linear accelerator, Siemens Somatom Open CT simulator and Elekta Monaco TPS. A 2D detector array was used to evaluate dose distribution accuracy in homogeneous, semi-anthropomorphic and anthropomorphic phantoms. Validation was based on gamma analysis with 3%/3mm and 2%/2mm criteria, respectively. Results Passing rates of the complex dose distributions degrade depending on the thickness of non-water equivalent material. They also depend on dose reporting mode used. It is observed that the passing rate decreases with plan complexity. Comparison of the data for all set-ups of semi-anthropomorphic and anthropomorphic phantoms shows that passing rates are higher in the anthropomorphic phantom. Conclusions Presented results raise a question of possible limits of dose distribution verification in assessment of plan delivery quality. Consequently, good results obtained using standard patient specific dosimetry methodology do not guarantee the accuracy of delivered dose distribution in real clinical cases
Keywords: IMRT, 2D dose verification, gamma method, antropomorphic phantom
Published in DiRROS: 10.06.2024; Views: 376; Downloads: 182
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1608. Interval cancers after negative immunochemical test compared to screen and non-respondersʼ detected cancers in Slovenian colorectal cancer screening programmeDominika Novak-Mlakar, Tatjana Kofol-Bric, Ana Lucija Škrjanec, Mateja Krajc, 2018, original scientific article Abstract: We assessed the incidence and characteristics of interval cancers after faecal immunochemical occult blood test and calculated the test sensitivity in Slovenian colorectal cancer screening programme. Patients and methods. The analysis included the population aged between 50 to 69 years, which was invited for screening between April 2011 and December 2012. The persons were followed-up until the next foreseen invitation, in average for 2 years. The data on interval cancers and cancers in non-responders were obtained from cancer registry. Gender, age, years of schooling, the cancer site and stage were compared among three observed groups. We used the proportional incidence method to calculate the screening test sensitivity. Results. Among 502,488 persons invited for screening, 493 cancers were detected after positive screening test, 79 interval cancers after negative faecal immunochemical test and 395 in non-responders. The proportion of interval cancers was 13.8%. Among the three observed groups cancers were more frequent in men (p = 0.009) and in persons aged 60+ years (p < 0.001). Comparing screen detected and cancers in non-responders with interval cancers more interval cancers were detected in persons with 10 years of schooling or more (p = 0.029 and p = 0.001), in stage III (p = 0.027) and IV (p < 0.001), and in right hemicolon (p < 0.001). Interval cancers were more frequently in stage I than non-responders cancers (p = 0.004). Test sensitivity of faecal immunochemical test was 88.45%. Conclusions. Interval cancers in Slovenian screening programme were detected in expected proportions as in similar programmes. Test sensitivity was among the highest when compared to similar programmes and was accomplished using test kit for two stool samples.
Keywords: cancer screening, colorectal cancer, faecal immunochemical test, test sensitivity
Published in DiRROS: 10.06.2024; Views: 315; Downloads: 87
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1609. Prevalence of BRAF, NRAS and c-KIT mutations in Slovenian patients with advanced melanomaMaja Ebert Moltara, Srdjan Novaković, Marko Boc, Marina Bučić, Martina Reberšek, Vesna Zadnik, Janja Ocvirk, 2018, original scientific article Abstract: BRAF, NRAS and c-KIT mutations are characteristics of tumour tissues that influence on treatment decisions in metastatic melanoma patients. Mutation frequency and their correlation with histological characteristics in Slovenian population have not been investigated yet. Patients and methods. In our retrospective analysis we analysed mutational status of BRAF, NRAS and c-KIT in 230 pathological samples of patients who were intended to be treated with systemic therapy due to metastatic disease at the Institute of Oncology Ljubljana between 2013 and 2016. We collected also histological characteristics of primary tumours and clinical data of patients and correlated them with mutational status of tumour samples. Results. The study population consisted of 230 patients with a mean age 59 years (range 25%85). 141 (61.3%) were males and 89 (38.7%) females. BRAF mutations were identified in 129 (56.1%), NRAS in 31 (13.5%) and c-KIT in 3 (1.3%) tissue samples. Among the 129 patients with BRAF mutations, 114 (88.4%) patients had V600E mutation and 15 (11.6%) had V600K mutation. Patients with BRAF mutations tended to be younger at diagnosis (52 vs. 59 years, p < 0.05), patients with NRAS mutations older (61 vs. 55 years, p < 0.05). Number of c-KIT mutations were too low for any statistical correlation, but there was one out of 3 melanoma located in mucus membranes. Conclusions. The analysis detected high rate of BRAF mutations, low NRAS mutations and low c-KIT mutations compared to previously published studies in Europe and North America. One of the main reasons for this observation is specific characteristics of study population.
Keywords: BRAF, NRAS, c-KIT, melanoma
Published in DiRROS: 10.06.2024; Views: 292; Downloads: 148
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1610. Ocular changes in metastatic melanoma patients treated with MEK inhibitor cobimetinib and BRAF inhibitor vemurafenibAna Uršula Gavrič, Janja Ocvirk, Polona Jaki Mekjavić, 2018, original scientific article Abstract: Mitogen-activated protein kinase kinase (MEK) inhibitor cobimetinib and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor vemurafenib have significantly improved the prognosis of BRAF-mutated metastatic melanoma. Some ocular symptoms and signs were recently recognized to follow this treatment. The study was aimed to investigate ocular toxicity in patients with metastatic melanoma treated with cobimetinib in combina-tion with vemurafenib.Patients and methods. In the prospective, observational study, patients with BRAF-mutated metastatic melanoma treated with cobimetinib in combination with vemurafenib at the Institute of Oncology Ljubljana were asked to par-ticipate. Ophthalmic examination was performed including measurement of visual acuity and intraocular pressure, slit lamp examination, funduscopy (CF), infrared-reflectance (IR) imaging and optical coherence tomography (OCT). Results. Five out of 7 patients noticed changes in vision few days after starting the therapy with cobimetinib. In all patients, small circular lesions, described as MEKAR lesions, were documented in outer retinal layers demonstrated with OCT, IR, and CF. Changes were in the center and/or scattered over the retina almost symmetrical in both eyes in 6 patients, and asymmetrical in one patient, the latter presented also with unilateral anterior uveitis and cystoid macular edema.Conclusions. Multiple bilateral foveal and extrafoveal small retinal lesions in the outer retinal layers develop in patients treated with MEK inhibitor in combination with BRAF inhibitor. Ophthalmologists and oncologists need to be aware of this common, yet relatively benign and often transient ocular side effect to avoid needless intervention, including the discontinuance of a potentially life-prolonging therapy.
Keywords: metastatic malignant melanoma, eye, MEK inhibitor, MEKAR
Published in DiRROS: 10.06.2024; Views: 357; Downloads: 143
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