1. The five-year KRAS, NRAS and BRAF analysis results and treatment patterns in daily clinical practice in Slovenia in 1st line treatment of metastatic colorectal (mCRC) patients with RASwild-type tumour (wtRAS) : a real- life data report 2013–2018Tanja Mesti, Martina Reberšek, Janja Ocvirk, 2023, original scientific article Abstract: Background. We preformed a Phase IV non-interventional study to assess KRAS, NRAS and BRAF status in metastatic colorectal cancer (mCRC) patients suitable for 1st line treatment and to evaluate the decisions for 1st line treatment considering the treatment goals in the RAS wild type (wt) patients. The aim of our study was also to evaluate the influ-ence of a waiting period for biomarkers analysis on the start of first-line treatment.Patients and methods. Patients with histologically confirmed mCRC adenocarcinoma suitable for first-line treat-ment fulfilling all inclusion criteria were included in the study. The KRAS, NRAS and BRAF analysis was performed from tissue samples of primary tumor site or metastatic site. All included patients have given consent to participate in the study by signing the informed consent form. Results. From April 2013 to March 2018 at the Institute of Oncology Ljubljana 650 patients were included, 637 of them were treated with first- line systemic treatment according to RAS and BRAF status. Remaining 13 patients with mCRC did not receive systemic first-line treatment. The distribution of patients with KRAS mutated and wild-type tumors, was almost equal, 48.8% and 47.9% respectively, 89 % of the patients had wt NRAS tumours and 86.1% had wt BRAF tu-mours. The most frequently prescribed treatment was bevacizumab-based therapy (53.1%), either in combination with doublet chemotherapy or with mono-chemotherapy. EGFR inhibitors cetuximab and panitumumab were prescribed in wt RAS mCRC patients (30.9%). The waiting period for biomarkers analysis was two weeks.Conclusions. Our real-world data, single centre 5-year analysis showed that the distribution between wild type and mutated type tumors of the patients with mCRC was approximately the same, as worldwide, so the Slovenian popula-tion with mCRC has the same ratio distribution of KRAS, NRAS and BRAF wild and mutated genes. We concluded that a two-week waiting period for biomarkers analysis did not influence the first line treatment decision, so it was in the accordance with the worldwide treatment guidelines based on evidence-based medicine.
Keywords: metastatic colorectal cancer, RAS and BRAF biomarkers, systemic treatment
Published in DiRROS: 25.07.2024; Views: 19; Downloads: 3
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2. Adverse events during immunotherapy in Slovenian patients with metastatic melanoma reveal a positive correlation with better treatment outcomesTanja Mesti, Vid Čeplak Mencin, Biljana Mileva Boshkoska, Janja Ocvirk, 2021, original scientific article Abstract: Background. Immunotherapy with CTLA-4 inhibitors and PD1 checkpoint inhibitors has initiated a breakthrough in the treatment and prognosis of patients with metastatic melanoma. The survival of these patients has increased from the expected survival time of less than 12 months to at least forty months. However, immunotherapy with either anti-CTLA-4 antibodies or PD1 inhibitors alone or in combination has a broad palette of significant immune-related adverse events. The aim of the study was to assess the correlation of immune-related adverse events with treatment outcomes defined as significant differences in the overall response rate (ORR) and progression-free survival (PFS) of patients, who developed immune-related adverse events during immunotherapy.Patients and methods. A retrospective analysis of patients with metastatic melanoma treated with immuno-therapy in 2020 at the Oncology Institute of Ljubljana was performed. Only patients with radiological evaluation of the immunotherapy response were included. The patients were divided into two cohorts: a cohort of patients with immune-related adverse events (irAE group) and a cohort of patients with no immune-related adverse events (NirAE group). Significantly better overall response and progression-free survival in the irAE cohort defined the primary aim of our study. To investigate the differences in progression-free survival between the irAE cohort and NirAE cohort, we used survival analysis. In particular, a Cox proportional hazards model with covariates of time to progression and adverse events was used for survival analysis. The Kruskal-Wallis H-test was applied, and a p-value of p <= 0.05 was considered the cut-off point for a statistically significant difference between the groups.Results. Among the 120 patients treated with immunotherapy, radiological response evaluation was performed for 99 patients: 38 patients in the irAE cohort and 61 patients in the NirAE cohort. The ORRs for the irAE and NirAE cohorts were 57% and 37%, respectively. The PFS was significantly better for the irAE cohort (301.6 days) than for the NirAE co-hort (247.29 days). The results of the survival regression analysis showed a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.Conclusions. Patients with metastatic melanoma treated with immunotherapy who developed immune-related adverse events showed better treatment outcomes with longer times to disease progression and better overall re-sponse rates than patients treated with immunotherapy who did not develop immune-related adverse events, with a significant increase in the survival probability from less than 60% for the NirAE cohort to almost 80% for the irAE cohort.
Keywords: immune related adverse events, immunotherapy, metastases, melanoma
Published in DiRROS: 22.07.2024; Views: 24; Downloads: 12
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3. Retrospective analysis of treatment-naive Slovenian patients with metastatic melanoma treated with pembrolizumab : real-world experienceNežka Hribernik, Marko Boc, Janja Ocvirk, Jasna Knez Arbeiter, Tanja Mesti, Marija Ignjatović, Martina Reberšek, 2020, original scientific article Abstract: Based on recent data from clinical trials, the immune checkpoint inhibitor pembrolizumab prolongs survival and has a good toxicity profile in patients with advanced or metastatic melanoma. However, the question remains whether these results are transmitted into daily clinical practice. The aim of this study was to assess the efficacy and toxicity of pembrolizumab in treatment-naive patients with metastatic melanoma in everyday clinical practice in Slovenia and compare it to the results from clinical trials. Patients and methods. This observational retrospective cohort study included 138 consecutive metastatic treatment-naive melanoma patients treated with pembrolizumab at the Institute of Oncology Ljubljana in Slovenia, from January 2016 to December 2018. Patient and treatment characteristics were retrospectively collected from hospital data base. Statistical data was obtained using the SPSS software version 22. Survival rate was calculated with the Kaplan-Meier method. Observation period took place between January 2016 and the end of June 2019. Results. The estimated median overall survival (OS) was 25.1 months (95% CI, 14.6%35.6) and the median progressionfree survival (PFS) was 10.7 months (95% CI, 5.9%15.4). Among all patients, 29 (21.0%) achieved complete response, 31 (22.5%) partial response and 23 (16.7%) reached stable disease. The number of organs with metastatic involvement and the level of baseline lactate dehydrogenase (LDH) concentration had significant influence on survival rates. Immune-related adverse events (irAE) were reported in 88 (63%) patients, while grade 3%4 irAE occurred in 12 (8.7%). Due to toxicity, 16 (11.6%) patients discontinued the treatment. Conclusions. Our real-world data from single centre retrospective analysis of treatment-naive metastatic melanoma patients treated with pembrolizumab showed inferior median OS and similar median PFS, compared to the results from clinical trials. However, patients with normal serum levels of LDH and a small number of organs with metastatic involvement had comparable survival outcomes. Toxicity rates of pembrolizumab were quite similar. These results further support the use of pembrolizumab for metastatic treatment-naive melanoma patients.
Keywords: immunotherapy, pembrolizumab, metastatic melanoma, treatment-naive
Published in DiRROS: 11.07.2024; Views: 76; Downloads: 34
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6. 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: 92; Downloads: 37
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7. 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: 123; Downloads: 62
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8. 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: 106; Downloads: 33
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9. Bevacizumab plus chemotherapy in elderly patients with previously untreated metastatic colorectal cancer : single center experienceJanja Ocvirk, Maja Ebert Moltara, Tanja Mesti, Marko Boc, Martina Reberšek, Neva Volk, Jernej Benedik, Zvezdana Hlebanja, 2016, original scientific article Abstract: Metastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients% register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer. Patients and methods. The registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories. Results. Between January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1st line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1st line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (% 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7%16.2) and 11.3 (95% CI, 10.2%12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4%28.9) and 27.4 (95% CI, 22.7%31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21/22 %, hypertension 25/19 %, haemorrhage 2/4 % and thromboembolic events 10/6 %, for elderly and < 70 years group, respectively. Conclusions. In routine clinical practice, the combination of bevacizumab and chemotherapy is effective and welltolerated regimen in elderly patients with metastatic colorectal cancer.
Keywords: metastatic colorectal cancer, bevacizumab, chemotherapy, elderly
Published in DiRROS: 30.04.2024; Views: 298; Downloads: 86
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10. Malignant gliomas : old and new systemic treatment approachesTanja Mesti, Janja Ocvirk, 2016, review article Abstract: Malignant (high-grade) gliomas are rapidly progressive brain tumours with very high morbidity and mortality. Until recently, treatment options for patients with malignant gliomas were limited and mainly the same for all subtypes of malignant gliomas. The treatment included surgery and radiotherapy. Chemotherapy used as an adjuvant treatment or at recurrence had a marginal role. Conclusions. Nowadays, the treatment of malignant gliomas requires a multidisciplinary approach. The treatment includes surgery, radiotherapy and chemotherapy. The chosen approach is more complex and individually adjusted. By that, the effect on the survival and quality of life is notable higher.
Keywords: malignant gliomas, systemic treatment, multidisciplinary, survival
Published in DiRROS: 30.04.2024; Views: 268; Downloads: 89
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