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3. Rak neznanega izvora : nas izvor bolezni še zanimaErika Matos, Snežana Pavlović Djokić, Srdjan Novaković, Marina Čakš, Rok Devjak, Nežka Hribernik, Kaja Cankar, 2024, professional article Abstract: Rak neznanega izvora (RNI) je opredeljen kot karcinom ali nediferencirana neoplazma, pri kateri z naborom standardnih diagnostičnih postopkov ni mogoče odkriti izvornega mesta bolezni. Tradicionalno RNI delimo v dve podskupini, pri čemer le približno 15 % primerov predstavlja prognostično ugodno skupino. Velika večina bolnikov spada v prognostično neugodno skupino in ima ob prvi prezentaciji obsežno breme bolezni. Možnosti zdravljenja so omejene, izidi bolnikov, zdravljenih z empirično kemoterapijo (KT) s platino ali taksani, pa so še vedno slabi, srednje celokupno preživetje je manj kot 10 mesecev. Za mnoge bolnike ostaja optimalna izbira najboljše možno podporno zdravljenje. Novi pristopi k obravnavi teh bolnikov se zdijo obetavni in so temeljit premik v paradigmi zdravljenja RNI; od zdravljenja, specifičnega za organ/tkivo, k zdravljenju, usmerjenemu na posameznega bolnika, ki temelji na genomskih spremembah njegovega tumorja. Prispevek povzema trenutne dokaze o uporabi vsakega od teh pristopov. Predstavljeno je tudi zdravljenje treh bolnikov z neugodnim RNI.
Keywords: rak neznanega izvora, molekularne značilnosti, biološki označevalci
Published in DiRROS: 26.07.2024; Views: 572; Downloads: 211
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4. Correlation of t(14;18) translocation breakpoint site with clinical characteristics in follicular lymphomaMatej Panjan, Lučka Boltežar, Srdjan Novaković, Ira Koković, Barbara Jezeršek Novaković, 2023, original scientific article Abstract: Background: t(14;18)(q32;q21) translocation is an important genetic feature of follicular lymphoma resulting in antiapoptotic B-cell lymphoma 2 (BCL2) protein overexpression. On chromosome 18 breakpoint-site variation is high but does not affect BCL2. Breakpoint most commonly occurs at major breakpoint region (MBR) but may happen at minor cluster region (mcr) and between MBR and mcr at 3'MBR and 5'mcr. The aim of this study was to analyze the correlation of t(14;18)(q32;q21) breakpoint site with clinical characteristics in follicular lymphoma. Patients and methods: We included patients diagnosed with follicular lymphoma who received at least 1 cycle of systemic treatment and had the t(14;18)(q32;q21) translocation detected by polymerase chain reaction (PCR) at MBR, mcr or 3'MBR prior to first treatment. Among patients with different breakpoints, sex, age, disease grade, stage, B-symptoms, follicular lymphoma international prognostic index (FLIPI), presence of bulky disease, progression free survival and overall survival were compared. Results: Of 84 patients, 63 had breakpoint at MBR, 17 at mcr and 4 at 3'MBR. At diagnosis, the MBR group had a significantly lower disease stage than the mcr group. Although not significant, in the MBR group we found a higher progression-free survival (PFS) and overall survival (OS), lower grade, age, FLIPI, and less B-symptoms. Conclusions: Compared to patients with mcr breakpoint, those with MBR breakpoint seem to be characterised by more favourable clinical characteristics. However, a larger study would be required to support our observation.
Keywords: clinical characteristics, follicular lymphoma, t(14, 18) translocation
Published in DiRROS: 25.07.2024; Views: 435; Downloads: 267
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5. Association between PIK3CA activating mutations and outcomes in early-stage invasive lobular breast carcinoma treated with adjuvant systemic therapyDomen Ribnikar, Valentina Jerič Horvat, Ivica Ratoša, Zachary Veitch, Biljana Grčar-Kuzmanov, Srdjan Novaković, Erik Langerholc, Eitan Amir, Boštjan Šeruga, 2023, original scientific article Abstract: The aim of the study was to evaluate the independent prognostic role of PIK3CA activating mutationsand an association between PIK3CA activating mutations and efficacy of adjuvant endocrine therapy (ET) in patientswith operable invasive lobular carcinoma (ILC).Patients and methods.A single institution study of patients with early-stage ILC treated between 2003 and 2008 wasperformed. Clinicopathological parameters, systemic therapy exposure and outcomes (distant metastasis-free sur-vival [DMFS] and overall survival [OS]) were collected based on presence or absence of PIK3CA activating mutationin the primary tumor determined using a quantitative polymerase chain reaction (PCR)-based assay. An associationbetween PIK3CA mutation status and prognosis in all patient cohort was analyzed by Kaplan-Meier survival analysis,whereas an association between PIK3CA mutation and ET was analyzed in estrogen receptors (ER) and/or progester-one receptors (PR)-positive group of our patients by the Cox proportional hazards model.Results. Median age at diagnosis of all patients was 62.8 years and median follow-up time was 10.8 years. Among365 patients, PIK3CA activating mutations were identified in 45%. PIK3CA activating mutations were not associatedwith differential DMFS and OS (p = 0.36 and p = 0.42, respectively). In patients with PIK3CA mutation each year oftamoxifen (TAM) or aromatase inhibitor (AI) decreased the risk of death by 27% and 21% in comparison to no ET, re-spectively. The type and duration of ET did not have significant impact on DMFS, however longer duration of ET hada favourable impact on OS.Conclusions. PIK3CA activating mutations are not associated with an impact on DMFS and OS in early-stage ILC.Patients with PIK3CA mutation had a statistically significantly decreased risk of death irrespective of whether theyreceived TAM or an AI.
Keywords: invasive lobular carcinoma, PIK3CA mutation, endocrine therapy
Published in DiRROS: 25.07.2024; Views: 561; Downloads: 147
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6. CD56-positive diffuse large B-cell lymphoma : comprehensive analysis of clinical, pathological, and molecular characteristics with literature reviewGorana Gašljević, Lučka Boltežar, Srdjan Novaković, Vita Šetrajčič Dragoš, Barbara Jezeršek Novaković, Veronika Kloboves-Prevodnik, 2023, original scientific article Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. The expression of CD56 in DLBCL is highly unusual. Little is known about its incidence and clinical importance. So far, no genetic profiling was performed in CD56 positive DLBCL.Patients and methods. Tissue microarrays have been constructed, sectioned, and stained by H&E and immuno-histochemistry for 229 patients with DLBCL diagnosed 2008–2017. For CD56 positive cases, clinical data was collected including age at diagnosis, stage of the disease, International Prognostic Index (IPI) score, treatment scheme and number of chemotherapy cycles, radiation therapy, treatment outcome, and possible relapse of the disease. Overall survival (OS) and progression-free survival (PFS) were calculated. For four patients, RNA was extracted and targeted RNA (cDNA) sequencing of 125 genes was performed with the Archer FusionPlex Lymphoma kit.Results. CD56 expression was found in 7 cases (3%). The intensity of expression varied from weak to moderate focal, to very intensive and diffuse. All patients had de novo DLBCL. The median age at the time of diagnosis was 54.5 years. Five of them were women and 2 males. According to the Hans algorithm, 6 patients had the germinal centre B cells (GBC) type and one non-GBC (activated B-cell [ABC]) type, double expressor. Genetic profiling of four patients ac-cording to Schmitz’s classification showed that 1 case was of the BN2 subtype, 1 of EZB subtype, 2 were unclassified. The six treated patients reached a complete response and did not experience progression of the disease during the median follow-up period of 80.5 months.Conclusions. We report on one of the largest series of CD56+DLBCL with detailed clinicopathological data and for the first time described genetical findings in a limited number of patients. Our results show that CD56 expression is rare, but seems to be present in prognostic favourable subtypes of DLBCL not otherwise specified (NOS) as tested by immunohistochemical or genetic profiling
Keywords: diffuse large B-cell lymphoma, immunohistochemistry, lymphomas, CD56
Published in DiRROS: 25.07.2024; Views: 444; Downloads: 160
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7. The prevalence of occult ovarian cancer in the series of 155 consequently operated high risk asymptomatic patients : Slovenian population based studyAndreja Gornjec, Sebastjan Merlo, Srdjan Novaković, Vida Stegel, Barbara Gazić, Andraž Perhavec, Ana Blatnik, Mateja Krajc, 2020, original scientific article Abstract: We assessed the prevalence, localization, type and outcome of occult cancer at risk-reducing salpingo-oophorectomy or salpingectomy (RRSO) in asymptomatic carriers of pathogenic or likely pathogenic BRCA1/2 variants and high-risk BRCA1/2 negative women. Patients and methods. A retrospective analysis of all consecutive gynaecologic preventive surgeries from January 2009 to December 2015 was performed. Participants underwent genetic counselling and BRCA1/2 testing before the procedure. Data on clinical parameters, adjuvant treatment and follow-up were collected and analysed. Results. One hundred and fifty-five RRSO were performed in 110 BRCA1, 35 BRCA2 carriers of pathogenic or likely pathogenic variants and 10 high-risk BRCA1/2 negative women, at the mean age of 48.3 years. Nine occult cancers (9/155, 5.8%) were identified; eight in BRCA1 positive women and one in high-risk BRCA1/2 negative woman. We identified four non-invasive serous intraepithelial tubal carcinomas (3 in BRCA1 carriers and 1 in a high-risk BRCA1/2 negative woman) and five invasive tubo-ovarian high grade serous cancers (all detected in BRCA1 carriers). Only one out of nine patients (11.1%) with occult cancer had a slightly elevated CA-125 value preoperatively. Conclusions. A 5.8% prevalence of occult invasive and noninvasive tubo-ovarian serous cancer after RRSO was found in high risk asymptomatic and screen negative women. We conclude that RRSO should be performed in BRCA1/2 carriers and in high-risk BRCA1/2 negative women. Age of preventive gynaecologic surgery should be carefully planned, taking into account the completion of childbearing age and type of mutation. The results favour the tubal hypothesis of tubal origin of high grade serous ovarian and peritoneal cancer. Cytology result of peritoneal cavity washing was important for the decision making process in determining treatment. Cytology examination should be performed in all cases of RRSO. CA-125 assay did not prove to be an effective screening tool for early cancer detection in our patients.
Keywords: risk-reducing salpingo-oophorectomy, occult serous cancer, serous tubal intraepithelial cancer, BRCA1/2 pathogenic or likely pathogenic variant
Published in DiRROS: 12.07.2024; Views: 409; Downloads: 149
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8. Randomised trial of HPV self-sampling among non-attenders in the Slovenian cervical screening programme ZORA : comparing three different screening approachesUrška Ivanuš, Tine Jerman, Alenka Repše-Fokter, Iztok Takač, Veronika Kloboves-Prevodnik, Mateja Marčec, Uršula Salobir Gajšek, Maja Pakiž, Jakob Koren, Simona Hutter-Čelik, Kristina Gornik-Kramberger, Ulrika Klopčič, Rajko Kavalar, Simona Šramek Zatler, Biljana Grčar-Kuzmanov, Mojca Florjančič, Nataša Nolde, Srdjan Novaković, Mario Poljak, Maja Primic-Žakelj, 2018, original scientific article Published in DiRROS: 11.06.2024; Views: 521; Downloads: 406
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9. 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: 459; Downloads: 223
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10. Genetic counselling, BRCA1/2 status and clinico-pathologic characteristics of patients with ovarian cancer before 50 years of ageMirjam Cvelbar, Marko Hočevar, Srdjan Novaković, Vida Stegel, Andraž Perhavec, Mateja Krajc, 2017, original scientific article Abstract: In Slovenia like in other countries, till recently, personal history of epithelial ovarian cancer (EOC) has not been included among indications for genetic counselling. Recent studies reported up to 17% rate of germinal BRCA1/2 mutation (gBRCA1/2m) within the age group under 50 years at diagnosis. The original aim of this study was to invite to the genetic counselling still living patients with EOC under 45 years, to offer gBRCA1/2m testing and to perform analysis of gBRCA1/2m rate and of clinico-pathologic characteristics. Later, we added also the data of previously genetically tested patients with EOC aged 45 to 49 years. Patients and methods. All clinical data have to be interpreted in the light of many changes happened in the field of EOC just in the last few years: new hystology stage classification (FIGO), new hystology types and differentiation grades classification, new therapeutic possibilities (PARP inhibitors available, also in Slovenia) and new guidelines for genetic counselling of EOC patients (National Comprehensive Cancer Network, NCCN), together with next-generation sequencing possibilities. Results. Compliance rate at the invitation was 43.1%. In the group of 27 invited or previously tested patients with EOC diagnosed before the age of 45 years, five gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within the group was 18.5%. There were 4 gBRCA1 and 1 gBRCA2 mutations detected. In the extended group of 42 tested patients with EOC diagnosed before the age of 50 years, 14 gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within this extended, partially selected group was 33.3%. There were 11 gBRCA1 and 3 gBRCA2 mutations detected. Conclusions. The rate of gBRCA1/2 mutation in tested unselected EOC patients under the age of 50 years was higher than 10%, namely 18.5%. Considering also a direct therapeuthic benefit of PARP inhibitors for BRCA positive patients, there is a double reason to offer genetic testing to all EOC patients younger than 50 years. Regarding clinical data, it is important to perform their re-interpretation in everyday clinical practice, because this may influence therapeutic possibilities to be offered.
Keywords: ovarian cancer, BRCA 1/2, genetic counseling
Published in DiRROS: 24.05.2024; Views: 610; Downloads: 284
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