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Epidemiology and risk factors of self-reported systemic allergic reactions to a Hymenoptera venom in beekeepers worldwide : a protocol for a systematic review of observational studies
Tanja Carli, Igor Locatelli, Mitja Košnik, Andreja Kukec, 2022, pregledni znanstveni članek

Povzetek: Introduction Systemic allergic reaction (SAR) to a Hymenoptera venom is a potentially life-threatening disorder. The rate of SAR between beekeepers in comparison with a healthy individual is different. The risk for an SAR is particularly high in beekeepers due to their persistent or seasonal exposure to the stinging Hymenoptera. We aim to provide a critical appraisal and a synthesis of evidence-based data from epidemiological observational studies, focusing on SARs to a Hymenoptera venom and the associated risk factors for SARs in beekeepers worldwide. Methods and analysis Searching will include seven electronic databases for published studies without language restrictions, from inception up to 3 August 2021, and it will be rerun for all electronic databases prior publication. Only epidemiological observational studies in beekeepers will be included. The risk of bias in the included studies will be appraised by using the Joanna Briggs Institute Critical Appraisal Checklist for Analytical Cross-Sectional Studies and the Newcastle-Ottawa Scale, adapted for cross-sectional studies. For the certainty of evidence, the Grading of Recommendations Assessment, Development and Evaluation approach will be used. Qualitative synthesis will be presented in a tabulated format with the selected characteristics across primary studies and the main outcome of interest. A meta-analysis is planned to be performed if there will be a sufficient number of homogeneous studies with complete data. The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement will guide the reporting of this systematic literature review. Ethics and dissemination No ethics approval is needed to conduct the systematic literature review since it will be solely based on the published literature. Findings will be disseminated through the relevant conferences, peer-review and open-access journals.
Ključne besede: systemic allergic reaction (SAR), Hymenoptera venom, systematic literature review
Objavljeno v DiRROS: 31.08.2022; Ogledov: 138; Prenosov: 56
.pdf Celotno besedilo (276,77 KB)
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Solid cancer patients achieve adequate immunogenicity and low rate of severe adverse events after SARS-CoV-2 vaccination
Urška Janžič, Urška Bidovec, Katja Mohorčič, Loredana Mrak, Nina Fokter Dovnik, Marija Ivanović, Maja Ravnik, Marina Čakš, Erik Škof, Jerneja Debeljak, Peter Korošec, Matija Rijavec, 2022, izvirni znanstveni članek

Povzetek: Background: SARS-CoV-2 vaccination in cancer patients is crucial to prevent severe COVID-19 disease course. Methods: This study assessed immunogenicity of cancer patients on active treatment receiving mRNA-based SARS-CoV-2 vaccine by detection of anti-SARS-CoV-2 S1 IgG antibodies in serum, before, after the first and second doses and 3 months after a complete primary course of vaccination. Results were compared with healthy controls. Results: Of 112 patients, the seroconversion rate was 96%. A significant reduction in antibody levels was observed 3 months after vaccination in patients receiving immune checkpoint inhibitors versus control participants (p < 0.001). Adverse events were mostly mild. Conclusion: Immunogenicity after mRNA-based vaccine in cancer patients is adequate but influenced by the type of anticancer therapy. Antibody levels decline after 3 months, and thus a third vaccination is warranted.
Ključne besede: onkološko zdravljenje, imunogenost, osnovno cepljenje mRNA, čvrsti tumorji, anticancer treatment, immunogenicity, mRNA-based vaccination, solid cancer
Objavljeno v DiRROS: 24.06.2022; Ogledov: 282; Prenosov: 97
.pdf Celotno besedilo (2,03 MB)

Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform
Marie Morfouace, Silvia Novello, A. Stevovic, C. Dooms, Urška Janžič, Thierry Berghmans, Rafal Dziadziuszko, T. Gorlia, Enriqueta Felip, Benjamin Besse, 2022, izvirni znanstveni članek

Povzetek: Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.
Ključne besede: thoracic neoplasms -- Europe, lung neoplasms -- Europe, diagnostic screening programs -- Europe, malignancies, lung cancer
Objavljeno v DiRROS: 24.06.2022; Ogledov: 237; Prenosov: 149
.pdf Celotno besedilo (4,21 MB)
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Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP) : a retrospective analysis from an early access program
Oliver 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: 241; Prenosov: 197
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P14/ARF-positive malignant pleural mesothelioma : ǂa ǂphenotype with distinct immune microenvironment
Federica Pezzuto, Francesca Lunardi, Luca Vedovelli, Francesco Fortarezza, Loredana Urso, Federica Grosso, Giovanni Luca Ceresoli, Izidor Kern, Gregor Vlačić, Fiorella Calabrese, 2022, izvirni znanstveni članek

Povzetek: Introduction: The CDKN2A gene plays a central role in the pathogenesis of malignant pleural mesothelioma (MPM). The gene encodes for two tumor suppressor proteins, p16/INK4A and p14/ARF, frequently lost in MPM tumors. The exact role of p14/ARF in MPM and overall its correlation with the immune microenvironment is unknown. We aimed to determine whether there is a relationship between p14/ARF expression, tumor morphological features, and the inflammatory tumor microenvironment. Methods: Diagnostic biopsies from 76 chemo-naive MPMs were evaluated. Pathological assessments of histotype, necrosis, inflammation, grading, and mitosis were performed. We evaluated p14/ARF, PD-L1 (tumor proportion score, TPS), and Ki-67 (percentage) by immunohistochemistry. Inflammatory cell components (CD3+, CD4+, CD8+ T lymphocytes; CD20+ B-lymphocytes; CD68+ and CD163+ macrophages) were quantified as percentages of positive cells, distinguishing between intratumoral and peritumoral areas. The expression of p14/ARF was associated with several clinical and pathological characteristics. A random forest-based machine-learning algorithm (Boruta) was implemented to identify which variables were associated with p14/ARF expression. Results: p14/ARF was evaluated in 68 patients who had a sufficient number of tumor cells. Strong positivity was detected in 14 patients (21%) (11 epithelioid and 3 biphasic MPMs). At univariate analysis, p14/ARF-positive epithelioid mesotheliomas showed higher nuclear grade (G3) (p = 0.023) and higher PD-L1 expression (≥50%) (p = 0.042). The percentages of CD4 and CD163 in peritumoral areas were respectively higher and lower in p14/ARF positive tumors but did not reach statistical significance with our sample size (both p = 0.066). The Boruta algorithm confirmed the predictive value of PD-L1 percentage for p14/ARF expression in all histotypes. Conclusions: p14/ARF-positive epithelioid mesotheliomas may mark a more aggressive pathological phenotype (higher nuclear grade and PD-L1 expression). Considering the results regarding the tumor immune microenvironment, p14/ARF-negative tumors seem to have an immune microenvironment less sensitive to immune checkpoint inhibitors, being associated with low PD-L1 and CD4 expression, and high CD163 percentage. The association between p14/ARF-positive MPMs and PD-L1 expression suggests a possible interaction of the two pathways. Confirmation of our preliminary results could be important for patient selection and recruitment in future clinical trials with anticancer immunotherapy.
Ključne besede: lung -- cytology -- pathology, neoplasms, malignant mesothelioma, malignant pleural mesothelioma, tumor microenvironment
Objavljeno v DiRROS: 30.05.2022; Ogledov: 255; Prenosov: 174
.pdf Celotno besedilo (13,14 MB)
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Expression patterns and prognostic relevance of subtype-specific transcription factors in surgically resected small cell lung cancer : an international multicenter study
Zsolt Megyesfalvi, Nandor Barany, Andras Lantos, Zsuzsanna Valko, Orsolya Pipek, Christian Lang, Anna Schwendenwein, Felicitas Oberndorfer, Sandor Paku, Bence Ferencz, Izidor Kern, Mile Kovačević, Viktoria Laszlo, Balazs Dome, 2022, izvirni znanstveni članek

Povzetek: The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant) and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we have investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1 and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines reveal distinct vulnerability profiles defined by transcription regulators.
Ključne besede: Non-small-cell lung carcinoma, immunohistochemistry, molecular subtypes, prognostic relevance, expression pattern, neuroendocrine subtypes
Objavljeno v DiRROS: 27.05.2022; Ogledov: 264; Prenosov: 495
.pdf Celotno besedilo (4,37 MB)
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Carboxypeptidase cathepsin X defines a multifunctional role of gamma-enolase in cancer
Tjaša Vižin, Anja Pišlar, Ib Jarle Christensen, Hans Jørgen Nielsen, Pika Meško-Brguljan, Janko Kos, 2022, izvirni znanstveni članek

Povzetek: Gamma-enolase enzymatic activity is involved in glycolysis, a prevalent process in cancer cell metabolism. Additionally, gamma-enolase has a pro-survival function, exhibited through the active site at the C-terminal end of the molecule. This activity is regulated by cysteine peptidase cathepsin X, which cleaves two amino acids at C-terminal end of gamma-enolase. In clinical practice, the determination of gamma-enolase as a tumour marker does not differ between total, uncleaved and C-terminally cleaved forms. However, levels of uncleaved gamma-enolase alone may provide additional clinical information. In this study we analysed cathepsin X, C- terminally uncleaved and total gamma-enolase in tumour cell lines and sera from 255 patients with colorectal cancer (CRC) by western blot, immunoprecipitation, enzymatic activity, ELISAs and ECLIA. Results show that uncleaved gamma-enolase, rather than total gamma- enolase, exhibits different levels in cells, being the highest in those, derived from metastatic sites or highly invasive tumours. Gamma-enolase is secreted into the extracellular space predominantly as an uncleaved form and levels were congruent to those within the cells. Furthermore, levels of uncleaved gamma-enolase in cells are inversely related to cathepsin X protein level and its enzymatic activity. Uncleaved gamma-enolase is also predominant form in sera of patients with CRC. Both forms exhibit similar stage dependent distribution, with slightly elevated levels in stage IV patients. Higher levels of total gamma-enolase are significantly related to shorter survival in patients with metastatic CRC. Results support evidence of additional pro-survival function of gamma-enolase in cancer. Future studies should focus on analysis of uncleaved gamma-enolase in tumour samples, which may provide additional relations to clinical indicators of disease progression.
Ključne besede: cancer, cathepsin X, cell survival, gamma-enolase, prognosis
Objavljeno v DiRROS: 06.04.2022; Ogledov: 309; Prenosov: 215
.pdf Celotno besedilo (1,16 MB)
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Natural history of the hymenoptera venom sensitivity reactions in adults : study design
Simona Perčič, Lidija Bojanić, Mitja Košnik, Andreja Kukec, 2022, izvirni znanstveni članek

Povzetek: Background: Allergic reactions to Hymenoptera stings can have varying levels of severity, according to the Müller grading system. Methods: By an epidemiological concept, this is a retrospective cohort study. The observed cohort was represented by patients referred to the University Clinic Golnik due to Hymenoptera allergic reaction in the period from 1997 to 2015. From the immunological database of the University Clinic Golnik, we obtained laboratory data (sIgE, skin tests and basophil activation test). The clinical characteristics of patients were obtained from BIRPIS. With the help of a questionnaire, which was sent to each patient in the period from May 2019 to April 2021, we obtained epidemiological data. For the assessment of the association between the severity of allergic reaction for the observed outcome, the severity of the first allergic reaction after Hymenoptera sting was used. Other variables were grouped according to risk factors. Discussion: We will identify the risk factors that could play an important role in a severe systemic reaction: the aetiology of the Hymenoptera sting, sex, age, history and severity of previous systemic reactions, being re-stung in an interval of two months, the frequency of re-stings, atopy, genetic predisposition, preventive medication use, other medication use, beekeeping or living next to beehives and why immunotherapy was not taken. Laboratory data will also be analysed to determine if there is any association with laboratory tests and the severity of the allergic reactions after Hymenoptera stings. Conclusions: Several new approaches are introduced in the study design. The most important is that the protocol covers epidemiological data gained from the questionnaire, as well as clinical data gained from the Immunological database and BIRPIS database. We expect to obtain significant results that will explain the risk factors for the natural history of Hymenoptera sting allergic reactions and will help allergologists, as well as general doctors, when facing those patients allergic to Hymenoptera venom without immunotherapy.
Ključne besede: hymenoptera venom allergy, risk factors, epidemiological association
Objavljeno v DiRROS: 06.04.2022; Ogledov: 299; Prenosov: 148
.pdf Celotno besedilo (786,63 KB)

Dynamic contrast-enhanced MRI in malignant pleural mesothelioma : prediction of outcome based on DCE-MRI measurements in patients undergoing cytotoxic chemotherapy
Martina Vivoda Tomšič, Peter Korošec, Viljem Kovač, Sotirios Bisdas, Katarina Šurlan Popović, 2022, izvirni znanstveni članek

Povzetek: The malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy. Methods: Thirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient's outcome. Results: Patients with higher pretreatment ET and AATH-calculated Ktrans and ve values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated Ktrans and kep values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated Ktrans was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min-1). Conclusions: In the present study, higher pre-treatment ET-calculated Ktrans values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.
Ključne besede: cisplatin, magnetic resonance imaging, mesothelioma
Objavljeno v DiRROS: 06.04.2022; Ogledov: 448; Prenosov: 218
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SERPING1 variants and C1-INH biological function : a close relationship with C1-INH-HAE
Christian Drouet, Alberto López Lera, Arije Ghannam, Margarita López-Trascasa, Sven Cichon, Denise Ponard, Faidra Parsopoulou, Hana Grombirikova, Tomas Freiberger, Matija Rijavec, Camila Lopes Veronez, João Bosco Pesquero, Anastasios E. Germenis, 2022, pregledni znanstveni članek

Povzetek: Hereditary angioedema with C1 Inhibitor deficiency (C1-INH-HAE) is caused by a constellation of variants of the SERPING1 gene (n = 809; 1,494 pedigrees), accounting for 86.8% of HAE families, showing a pronounced mutagenic liability of SERPING1 and pertaining to 5.6% de novo variants. C1-INH is the major control serpin of the kallikrein–kinin system (KKS). In addition, C1-INH controls complement C1 and plasminogen activation, both systems contributing to inflammation. Recognizing the failed control of C1s protease or KKS provides the diagnosis of C1-INH-HAE. SERPING1 variants usually behave in an autosomal-dominant character with an incomplete penetrance and a low prevalence. A great majority of variants (809/893; 90.5%) that were introduced into online database have been considered as pathogenic/likely pathogenic. Haploinsufficiency is a common feature in C1-INH-HAE where a dominant-negative variant product impacts the wild-type allele and renders it inactive. Small (36.2%) and large (8.3%) deletions/duplications are common, with exon 4 as the most affected one. Point substitutions with missense variants (32.2%) are of interest for the serpin structure–function relationship. Canonical splice sites can be affected by variants within introns and exons also (14.3%). For noncanonical sequences, exon skipping has been confirmed by splicing analyses of patients' blood-derived RNAs (n = 25). Exonic variants (n = 6) can affect exon splicing. Rare deep-intron variants (n = 6), putatively acting as pseudo-exon activating mutations, have been characterized as pathogenic. Some variants have been characterized as benign/likely benign/of uncertain significance (n = 74). This category includes some homozygous (n = 10) or compound heterozygous variants (n = 11). They are presenting with minor allele frequency (MAF) below 0.00002 (i.e., lower than C1-INH-HAE frequency), and may be quantitatively unable to cause haploinsufficiency. Rare benign variants could contribute as disease modifiers. Gonadal mosaicism in C1-INH-HAE is rare and must be distinguished from a de novo variant. Situations with paternal or maternal disomy have been recorded (n = 3). Genotypes must be interpreted with biological investigation fitting with C1-INH expression and typing. Any SERPING1 variant reminiscent of the dysfunctional phenotype of serpin with multimerization or latency should be identified as serpinopathy.
Ključne besede: Hereditary angioedemas -- genetics -- diagnosis, genetic variation, serpins, SERPING1 gene, C1-INH, C1-INH-HAE, C1 inhibitor, serpinopathy
Objavljeno v DiRROS: 06.04.2022; Ogledov: 325; Prenosov: 211
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