High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer and is among the most fatal gynecological malignancies worldwide, due to late diagnosis at advanced stages and frequent therapy resistance. In 47 HGSC patients, we assessed somatic and germline genetic variability of a custom panel of 144 known or suspected HGSC-related genes by high-coverage targeted DNA sequencing to identify the genetic determinants associated with resistance to platinum-based therapy. In the germline, the most mutated genes were DNAH14 (17%), RAD51B (17%), CFTR (13%), BRCA1 (11%), and RAD51 (11%). Somatically, the most mutated gene was TP53 (98%), followed by CSMD1/2/3 (19/19/36%), and CFTR (23%). Results were compared with those from whole exome sequencing of a similar set of 35 HGSC patients. Somatic variants in TP53 were also validated using GENIE data of 1287 HGSC samples. Our approach showed increased prevalence of high impact somatic and germline mutations, especially those affecting splice sites of TP53, compared to validation datasets. Furthermore, nonsense TP53 somatic mutations were negatively associated with patient survival. Elevated TP53 transcript levels were associated with platinum resistance and presence of TP53 missense mutations, while decreased TP53 levels were found in tumors carrying mutations with predicted high impact, which was confirmed in The Cancer Genome Atlas data (n = 260). Targeted DNA sequencing of TP53 combined with transcript quantification may contribute to the concept of precision oncology of HGSC. Future studies should explore targeting the p53 pathway based on specific mutation types and co-analyze the expression and mutational profiles of other key cancer genes.

• Klíčová slova
• TP53, biomarkers, ovarian carcinoma, platinum resistance, treatment response,
• MeSH
• chemorezistence * genetika   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorový supresorový protein p53 * genetika   MeSH
• nádory vaječníků * genetika   farmakoterapie   patologie   MeSH
• platina terapeutické užití   farmakologie   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenování exomu metody   MeSH
• senioři MeSH
• serózní cystadenokarcinom * genetika   farmakoterapie   patologie   MeSH
• zárodečné mutace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• nádorový supresorový protein p53 * MeSH
• platina MeSH
• TP53 protein, human MeSH Prohlížeč

PURPOSE: The CD47 molecule, often referred to as the "do not eat me" signal, is frequently overexpressed in tumor cells. This signaling pathway limits phagocytosis by macrophages. Our objective was to determine CD47 abundance in various soft tissue sarcomas (STS) to investigate whether it could serve as a potential evasion mechanism for tumor cells. Additionally, we aimed to assess the prognostic value of CD47 expression by examining its association with different clinicopathological factors. This study aimed to elucidate the significance of CD47 in the context of emerging anti-tumor targeting approaches. METHODS: In this retrospective study, formalin-fixed paraffine-embedded (FFPE) tumor tissues of 55 treatment-naïve patients were evaluated by immunohistochemistry for the abundance of CD47 molecule on tumor cells. The categorization of CD47 positivity was as follows: 0 (no staining of tumor cells), 1 + (less than 1/3 of tumor area positive), 2 + (between 1/3 and 2/3 of tumor area positive), and 3 + (more than 2/3 of tumor area positive for CD47). Next, we compared CD47 abundance between different tumor grades (G1-3). We used Kaplan-Meier survival curves with log-rank test to analyze the differences in survival between patients with different CD47 expression. Moreover, we performed Cox proportional hazards regression model to evaluate the clinical significance of CD47. RESULTS: CD47 is widely prevalent across distinct STS subtypes. More than 80% of high grade undifferentiated pleiomorphic sarcoma (UPS), 70% of myxofibrosarcoma (MFS) and more than 60% of liposarcoma (LPS) samples displayed a pattern of moderate-to-diffuse positivity. This phenomenon remains consistent regardless of the tumor grade. However, there was a tendency for higher CD47 expression levels in the G3 group compared to the combined G1 + G2 groups when all LPS, MFS, and UPS were analyzed together. No significant associations were observed between CD47 abundance, death, and metastatic status. Additionally, high CD47 expression was associated with a statistically significant increase in progression-free survival in the studied cohort of patients. CONCLUSION: This study highlights the potential of the CD47 molecule as a promising immunotherapeutic target in STS, particularly given its elevated expression levels in diverse sarcoma types. Our data showed a notable trend linking CD47 expression to tumor grade, while also suggesting an interesting correlation between enhanced abundance of CD47 expression and a reduced hazard risk of disease progression. Although these findings shed light on different roles of CD47 in STS, further research is crucial to assess its potential in clinical settings.

• Klíčová slova
• CD47, Immune checkpoint inhibitors, Immunotherapy, Macrophages, Soft tissue sarcoma,
• MeSH
• antigeny CD47 metabolismus   MeSH
• dospělí MeSH
• lidé MeSH
• lipopolysacharidy MeSH
• makrofágy patologie   MeSH
• nádory měkkých tkání * patologie   MeSH
• prognóza MeSH
• retrospektivní studie MeSH
• sarkom * terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD47 MeSH
• CD47 protein, human MeSH Prohlížeč
• lipopolysacharidy MeSH

BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

• MeSH
• antitumorózní látky * škodlivé účinky   terapeutické užití   MeSH
• chinazoliny škodlivé účinky   terapeutické užití   MeSH
• lidé MeSH
• nádory štítné žlázy * farmakoterapie   genetika   MeSH
• piperidiny škodlivé účinky   terapeutické užití   MeSH
• progrese nemoci MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• pyridiny * škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antitumorózní látky * MeSH
• cabozantinib MeSH Prohlížeč
• chinazoliny MeSH
• piperidiny MeSH
• protoonkogenní proteiny c-ret MeSH
• pyridiny * MeSH
• RET protein, human MeSH Prohlížeč
• selpercatinib MeSH Prohlížeč
• vandetanib MeSH Prohlížeč

OBJECTIVES: This article estimates the cost-effectiveness of adding pertuzumab to the combination of trastuzumab and docetaxel within the first-line treatment for metastatic breast cancer with the amplification of HER2+. METHODS: Data from Czech clinical practice recorded in the BREAST register are used. A semi-Markov model with states derived based on the treatment phases (first-line medication, no medication, next-line medication, death) is defined to estimate costs from the healthcare payers' perspective. The benefits are estimated as patient survival until death. The Kaplan-Meier estimates are supplemented by the Cox proportional hazard and the accelerated failure time models to control for patient characteristics. Health-related quality-of-life indicators are derived from relevant literature. RESULTS: Based on the used data, adding pertuzumab does not result in statistically significantly longer survival while inducing higher treatment costs (€163 360 compared with €90 112 per patient in 2018 prices). Statistically longer survival was not supported by the log-rank test (P = .97), the Cox proportional hazard model, or the accelerated failure time model using the Gompertz distribution. The incremental cost-effectiveness ratio (€87 200) substantially exceeds the willingness to pay for 1 quality-adjusted life-year (€46 500). CONCLUSIONS: This analysis indicates that adding pertuzumab cannot be considered cost-effective in Czechia. However, the observed phenomenon may be attributed to the limited duration of patient follow-up periods at the time of the study's execution (mean of 20-21 months). Importantly, we find that using states connected to specific treatment phases is appropriate for a retrospective analysis of patient-level clinical data.

• Klíčová slova
• HER2+ metastatic breast cancer, cost states in semi-Markov process, cost-effectiveness, pertuzumab,
• MeSH
• analýza nákladů a výnosů MeSH
• lidé MeSH
• nádory prsu * farmakoterapie   MeSH
• receptor erbB-2 terapeutické užití   MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• pertuzumab MeSH Prohlížeč
• receptor erbB-2 MeSH

Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.

• MeSH
• cyklofosfamid škodlivé účinky   MeSH
• difúzní velkobuněčný B-lymfom * patologie   MeSH
• dospělí MeSH
• doxorubicin škodlivé účinky   MeSH
• lenalidomid terapeutické užití   MeSH
• lidé MeSH
• myší monoklonální protilátky škodlivé účinky   MeSH
• prednison škodlivé účinky   MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• rituximab škodlivé účinky   MeSH
• vinkristin škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• cyklofosfamid MeSH
• doxorubicin MeSH
• lenalidomid MeSH
• myší monoklonální protilátky MeSH
• prednison MeSH
• rituximab MeSH
• tafasitamab MeSH Prohlížeč
• vinkristin MeSH

Oxysterols, oxidized derivatives of cholesterol, act in breast cancer (BC) as selective estrogen receptor modulators and affect cholesterol homeostasis, drug transport, nuclear and cell receptors, and other signaling proteins. Using data from three highly overlapping sets of patients (N = 162 in total) with early-stage estrogen-receptor-positive luminal BC-high-coverage targeted DNA sequencing (113 genes), mRNA sequencing, and full micro-RNA (miRNA) transcriptome microarrays-we describe complex oxysterol-related interaction (correlation) networks, with validation in public datasets (n = 538) and 11 databases. The ESR1-CH25H-INSIG1-ABCA9 axis was the most prominent, interconnected through miR-125b-5p, miR-99a-5p, miR-100-5p, miR-143-3p, miR-199b-5p, miR-376a-3p, and miR-376c-3p. Mutations in SC5D, CYP46A1, and its functionally linked gene set were associated with multiple differentially expressed oxysterol-related genes. STARD5 was upregulated in patients with positive lymph node status. High expression of hsa-miR-19b-3p was weakly associated with poor survival. This is the first study of oxysterol-related genes in BC that combines DNA, mRNA, and miRNA multiomics with detailed clinical data. Future studies should provide links between intratumoral oxysterol signaling depicted here, circulating oxysterol levels, and therapy outcomes, enabling eventual clinical exploitation of present findings.

• Klíčová slova
• breast cancer, integrative analysis, interaction network, multiomics, oxysterols, survival,
• MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádory prsu * patologie   MeSH
• oxysteroly * MeSH
• transkriptom genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• messenger RNA MeSH
• mikro RNA * MeSH
• oxysteroly * MeSH

INTRODUCTION: Glomus jugulare tumours (GJT) are benign tumours that arise locally and destructively in the base of the skull and can be successfully treated with radiotherapy. Patients have a long-life expectancy and the late effects of radiotherapy can be serious. Proton radiotherapy reduces doses to critical organs and can reduce late side effects of radiotherapy. The aim of this study was to report feasibility and early clinical results of 12 patients treated using proton therapy. METHODS: Between December 2013 and June 2019, 12 patients (pts) with GJT (median volume 20.4 cm3 ; range 8.5-41 cm3 ) were treated with intensity modulated proton therapy (IMPT). Median dose was 54 GyE (Gray Equivalents) (50-60 GyE) with daily fractions of 2 GyE. Twelve patients were analysed with a median follow-up time of 42.2 months (11.3-86.7). Feasibility, dosimetric parameters, acute and late toxicity and local effect on tumour were evaluated in this retrospective study. RESULTS: All patients finished treatment without interruption, with excellent dosimetric parameters and mild acute toxicity. Stabilisation of tumour size was detected on MRI in all patients. No changes in symptoms were observed in comparison with pre-treatment conditions. No late effects of radiotherapy were observed. CONCLUSION: Pencil-beam scanning proton radiotherapy is highly feasible in the treatment of large GJT with mild acute toxicity and promising short-term results. Longer follow-up and larger patient cohorts are required to further identify the role of pencil-beam scanning (PBS) for this indication.

• Klíčová slova
• Head and neck, glomus jugulare, proton radiotherapy, radiation oncology,
• MeSH
• celková dávka radioterapie MeSH
• lidé MeSH
• plánování radioterapie pomocí počítače metody   MeSH
• protonová terapie * škodlivé účinky   metody   MeSH
• protony MeSH
• radioterapie s modulovanou intenzitou * škodlivé účinky   metody   MeSH
• retrospektivní studie MeSH
• tumor glomus jugulare * etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• protony MeSH

BACKGROUND: As a system of European Reference Networks (ERNs) emerges, the differences in quality of care for patients with rare cancers may increase at national level. We aimed to elucidate the processes and healthcare planning principles through which the reference centres (RCs) for rare cancers are embedded in national health systems. METHODS: We used a multiple case-study design based on the experiences of Czechia, Finland, France, Italy, Lithuania and Spain. Using sarcoma as an example of rare cancer, 52 semi-structured interviews were conducted during on-site visits, including a multidisciplinary group of professionals, Ministry of Health professionals, patient representatives and European policymakers. RESULTS: The comparative analysis showed substantial heterogeneity in the processes for formalizing RCs' status and in their levels of integration in the different health systems, but two models (centre-based and the network-based) can be envisaged at national level. RCs for rare cancers were legally established only in France and Spain. Expert clinicians cooperate in a structured way, using network mechanisms, in France and Italy, and these countries, plus Finland and Lithuania, had a referral system to facilitate patients' access from non-expert centres to RCs. Seven key healthcare planning principles in instituting RCs at the national level were identified. CONCLUSIONS: The conditions governing patient access to treatment centres-whether RCs or not-are decided at the national level. It is advisable to progressively align the European and national levels so that the RCs that participate in the ERNs also play a significant role at the national level.

• MeSH
• konziliární vyšetření a konzultace MeSH
• lidé MeSH
• nádory * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Francie MeSH
• Itálie MeSH
• Španělsko MeSH

INTRODUCTION: Human kinesin 14 (KIF14) is one of the 70 prognostic marker genes (so-called Amsterdam profile) previously identified by the microarray of breast carcinomas, and its high transcript expression in tumor specimens indicates a poor prognosis for patients. We performed a pilot study to explore the prognostic and predictive meaning of KIF14 germline genetic variability in breast cancer patients. METHODS: KIF14 coding sequence, including 5' and 3' untranslated regions and overlaps to introns for identification of splicing sites, was analyzed using next-generation sequencing in the testing set of blood DNA samples from 105 breast cancer patients with clinical follow-up. After rigorous evaluation of major allele frequency, haplotype blocks, in silico predicted functional aspects, expression quantitative trait loci, and clinical associations, eight single nucleotide variants were subsequently validated in the evaluation set of 808 patients. RESULTS: Carriers of minor alleles G (rs17448931) or T (rs3806362) had significantly shorter overall survival than wild type homozygotes (p = 0.010 and p = 0.023, respectively) thus successfully replicating the results of the testing set. Both associations remained significant in the multivariate Cox regression analysis, including molecular subtype and stage as covariates (hazard ratio, HR = 1.7, 95% confidence interval (CI) = 1.1-2.8 for rs17448931 and HR = 1.9, CI 1.2-3.0 for rs3806362). DISCUSSION: In conclusion, our preliminary data suggest that minor alleles in rs17448931 and rs3806362 of KIF14 represent candidate biomarkers of poor prognosis of breast cancer patients. After pending validation in independent populations and eventual functional characterization, these candidates might become useful biomarkers in the clinics.

• MeSH
• kineziny * MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory prsu * patologie   MeSH
• nukleotidy MeSH
• onkogenní proteiny genetika   metabolismus   MeSH
• pilotní projekty MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• KIF14 protein, human MeSH Prohlížeč
• kineziny * MeSH
• nádorové biomarkery MeSH
• nukleotidy MeSH
• onkogenní proteiny MeSH

Oxysterols, oxidized derivatives of cholesterol, have been implicated in multiple pathologies, including cancer. In breast cancer, the link is especially strong due to interactions between oxysterols and estrogen receptor activity. Here, we provide the first dedicated study of 113 oxysterol-related genes in breast cancer patients of the luminal subtype, in terms of both their somatic and germline variability, using targeted high-throughput DNA sequencing of 100 normal-tumor pairs with very high coverage. In the full cohort, or subsets of patients stratified by therapy, we found 12 germline variants in ABCA1, ABCA8, ABCC1, GPR183, LDLR, MBTPS1, NR1I2, OSBPL2, OSBPL3, and OSBPL5 to associate with poor survival of patients and variants in ABCA8, ABCG2, and HSD3B7 (three in total) associated with better survival. However, no associations remained significant after correction for multiple tests. Analysis of somatic variants revealed significantly (after FDR correction) poorer survival in patients mutated in CYP46A1 and 9 interacting (according to STRING analysis) genes, as well as in OSBPL3 and a set of 20 genes that collectively associated with the progesterone receptor status of patients. We propose further exploration of these genes in an integrative manner together with gene expression and epigenomic data.

• Klíčová slova
• Breast cancer, Genomics, Mutation, Oxysterols, Prognosis, Variant,
• MeSH
• kohortové studie MeSH
• lidé MeSH
• nádory prsu * genetika   patologie   MeSH
• oxysteroly * metabolismus   MeSH
• steroidní receptory * genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• zárodečné buňky metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• OSBPL2 protein, human MeSH Prohlížeč
• oxysteroly * MeSH
• steroidní receptory * MeSH