Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)-related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by EPHA7, ATM, GRIN2A, and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.

• MeSH
• ATM protein genetika   MeSH
• dospělí MeSH
• erbB receptory genetika   MeSH
• infekce papilomavirem MeSH
• inhibitor p16 cyklin-dependentní kinasy genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory penisu * genetika   mortalita   patologie   virologie   MeSH
• prognóza MeSH
• proteiny vázající telomery MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• shelterinový komplex MeSH
• spinocelulární karcinom * genetika   mortalita   patologie   virologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

Pathogenic alterations, namely, fusions and amplifications, of the GLI1 gene have been identified in various mesenchymal tumors, including pericytoma with t(7;12), plexiform fibromyxoma, gastroblastoma, and other malignant mesenchymal neoplasms arising in the soft tissues, as well as in various visceral organs. However, only three cases of GLI1-rearranged renal tumors have been reported to date, comprising two low-grade spindle cell tumors with GLI1::FOXO4 fusion along with one GLI1-rearranged case with an unknown fusion partner. In this study, we analyzed three cases with GLI1::FOXO4 fusion and overlapping morphology. One of the cases was reported previously, but an extended clinical and immunohistochemical information is provided. The studied cases occurred in 2 female and 1 male patients aged 35, 55, and 62 years (mean 51 years). All three tumors affected the renal parenchyma and grew as unencapsulated but well-circumscribed solid masses containing occasional entrapped and dilated renal tubules. The tumor cells were organized in cords, nests, or fascicles, had a round to spindled shape, and exhibited only mild nuclear atypia and minimal mitotic activity. They had a sparse eosinophilic to clear cytoplasm and were embedded in myxocollagenous stroma. Immunohistochemically, all cases expressed GLI1 (albeit with variable intensity) and harbored GLI1::FOXO4 fusion. All three patients were treated solely by complete surgical excision. Case 1 was alive with unknown disease status, case 2 was alive without evidence of disease, and case 3 died of unrelated causes. Our study doubles the number of reported cases with GLI1::FOXO4 fusion. The so far absolute predilection of this fusion for renal tumors, coupled with the absence of reports of other GLI1 fusions in tumors of the kidney, might indicate the potential existence of a distinct renal subtype with morphological features similar to other GLI1-altered tumors. All four reported cases had an uneventful follow-up which, together with their low-grade morphological features, suggests that these tumors might have a favorable prognosis.

• MeSH
• dospělí MeSH
• forkhead transkripční faktory * genetika   MeSH
• genová přestavba * MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery * genetika   analýza   MeSH
• nádory ledvin * genetika   patologie   MeSH
• protein Gli1 * genetika   MeSH
• proteiny buněčného cyklu * genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: The knowledge and proficiency of primary care practitioners (PCPs) in diagnosing and managing irritable bowel syndrome (IBS) remain generally low and variable internationally. This variability is partly due to a lack of familiarity with the Rome Foundation diagnostic criteria and treatment guidelines for this condition. METHODS: We conducted an electronic survey of PCPs in the United States and nine European countries to assess their understanding of IBS pathophysiology; the use of Rome IV criteria in diagnosis, knowledge of and frequency in prescribing various recommended treatments; and the likelihood of referring patients with suspected IBS to subspecialists. RESULTS: Most PCPs in the United States and Europe perceive IBS as a diagnosis of exclusion rather than a definitive diagnosis. They also believe IBS is underdiagnosed in primary care and challenging to diagnose confidently. The majority of PCPs consider diet as a crucial component of IBS management. Notably, US PCPs reported greater confidence than their European counterparts in recommending dietary interventions such as increased dietary fiber, a low FODMAP diet, and gluten restriction. Conversely, both groups exhibited moderate to high confidence in recommending over-the-counter treatments. European PCPs showed greater confidence in treating IBS with antispasmodics and secretagogues, while US PCPs expressed greater confidence in prescribing neuromodulators. Additionally, US PCPs were more likely to refer patients with suspected IBS to a gastroenterologist, whereas both US and European PCPs showed similar referral patterns to dietitians and referred very few patients to mental health providers. Both US and European PCPs reported that IBS is moderately to extremely difficult to treat effectively and emphasized the importance of a strong and longitudinal doctor-patient relationship in managing the condition. CONCLUSION: Despite the Rome Foundation recommendations and criteria to support a positive diagnosis of IBS, most PCPs still rely on exclusionary investigations such as endoscopy and a serologic workup, while a significant percentage suggest referring patients to gastroenterologists.

• MeSH
• lékaři primární péče MeSH
• lékařská praxe - způsoby provádění * statistika a číselné údaje   MeSH
• lidé MeSH
• postoj zdravotnického personálu MeSH
• primární zdravotní péče MeSH
• průzkumy a dotazníky MeSH
• syndrom dráždivého tračníku * diagnóza   terapie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Spojené státy americké MeSH

The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

• MeSH
• dlaždicobuněčné karcinomy hlavy a krku virologie   patologie   genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• fúzní onkogenní proteiny genetika   MeSH
• infekce papilomavirem * patologie   komplikace   genetika   virologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory hlavy a krku * patologie   virologie   genetika   MeSH
• proteiny asociované s mikrotubuly genetika   MeSH
• receptor fibroblastových růstových faktorů, typ 3 * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spinocelulární karcinom patologie   genetika   virologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. METHODS AND RESULTS: Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic small round cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. CONCLUSIONS: DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

• MeSH
• dítě MeSH
• dospělí MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• genová přestavba MeSH
• homeodoménové proteiny * metabolismus   genetika   MeSH
• imunohistochemie * MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery * metabolismus   analýza   genetika   MeSH
• nádory měkkých tkání diagnóza   patologie   genetika   metabolismus   MeSH
• předškolní dítě MeSH
• sarkom * diagnóza   patologie   genetika   metabolismus   MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.

• MeSH
• aktivátory chloridových kanálů terapeutické užití   farmakologie   MeSH
• aminofenoly * terapeutické užití   farmakologie   MeSH
• benzodioxoly * terapeutické užití   farmakologie   MeSH
• chinolony * farmakologie   terapeutické užití   MeSH
• cystická fibróza * genetika   farmakoterapie   MeSH
• fixní kombinace léků MeSH
• indoly * farmakologie   MeSH
• lidé MeSH
• organoidy * metabolismus   MeSH
• protein CFTR genetika   MeSH
• pyrazoly * farmakologie   MeSH
• pyridiny farmakologie   MeSH
• pyrrolidiny farmakologie   MeSH
• pyrroly farmakologie   MeSH
• stanovení celkové genové exprese metody   MeSH
• střeva účinky léků   MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cíl: Cílem naší práce bylo popsat epidemiologickou situaci výskytu rotavirových gastroenteritid (RG) a vliv očkování na hospitalizaci pro RG v České republice (ČR) v letech 2018–2023. Metody: Byla provedena deskriptivní analýza anonymizovaných případů RG hlášených pod kódem A08.0 v systému pro hlášení infekčních onemocnění (ISIN) v České republice v letech 2018–2023. K analýze binárních proměnných byl použit chí-kvadrát test. Vliv očkování na hospitalizaci byl hodnocen pomocí logistické regrese s odds ratio (OR) a 95 % intervalu spolehlivosti. Použity byly programy Excel, STATA a Datawrapper GmbH. Incidence onemocnění byla přepočítána na 100 000 obyvatel. Výsledky: Ve sledovaném období bylo v ČR hlášeno celkem 26 303 případů RG (v rozmezí 1 811–7 483 ročně), což odpovídá průměrné roční incidenci 41,0 (rozmezí 16,9–69,6) na 100 000 obyvatel. Padesát jedna procent případů se vyskytlo u žen. Průměrná roční specifická incidence podle pohlaví byla srovnatelná. Případy se vyskytly u osob 0–101letých (medián 3 roky, mezikvartilové rozpětí [IQR] 1–8 let). Maximální počty případů byly zaznamenány v měsících březen až červen, přičemž v pandemických letech 2020 a 2021 byly celkové počty případů nižší, a tedy i sezonnost byla vyjádřena méně. Průměrná roční specifická incidence byla nejvyšší v krajích Vysočina, Jihočeském a Olomouckém. Hospitalizováno bylo 18 693 (71,1 %) případů RG, nejvíce případů ve věkové skupině 1–4 roky (34,7 %) a 5–9 let (11,9 %). Údaje o očkování byly dostupné pro 21 142 osob s RG, z nich 304 (1,4 %) osob bylo vykázáno jako očkováno. Riziko hospitalizace pro RG bylo u očkovaných osob statisticky významně nižší (p < 0,001) než u neočkovaných. Nahlášeno bylo celkem 27 epidemií RG, v největší bylo zaznamenáno 152 případů. Jako import bylo hlášeno 226 případů onemocnění. Závěr: Po zahájení očkování proti RG v ČR bylo očekáváno snížení počtu onemocnění, hospitalizací a úmrtí pro tato onemocnění. Nicméně významný dopad očkování na zátěž RG dosud v ČR pozorován není a domníváme se, že hlavním důvodem je nadále nízká proočkovanost proti RG v ČR. Doporučujeme proto zařadit toto dobrovolné očkování mezi očkování hrazená zdravotními pojišťovnami a zároveň apelujeme na časnou komunikaci vhodnosti očkování mezi praktickým lékařem pro děti a dorost a rodiči dětí.

Aim: To describe the epidemiological situation of rotavirus gastroenteritis (RVGE) and the impact of vaccination on hospitalization for RVGE in the Czech Republic in 2018–2023. Methods: A descriptive analysis was performed of anonymized RVGE cases reported under code A08.0 to the Infectious Diseases Reporting System (ISIN) in the Czech Republic in 2018–2023. The Chi-square test was used to analyse binary variables. The effect of vaccination on hospitalization was assessed using logistic regression with odds ratio (OR) and 95% confidence interval. Excel, STATA, and Datawrapper GmbH programs were used. The incidence of the disease was calculated per 100,000 population. Results: In the monitored period, a total of 26,303 RVGE cases were reported in the Czech Republic (range 1,811–7,483 per year), which corresponds to an average annual incidence of 41.0 (range 16.9–69.6) per 100,000 population. Fifty-one percent of cases occurred in women. The average annual sex-specific incidence rates were comparable. Patients were aged 0–101 years (median 3 years, interquartile range [IQR] 1–8 years). The maximum numbers of cases were recorded in the months of March to June. In the pandemic years 2020 and 2021, the overall numbers of cases were lower, and therefore the seasonality was less expressed. The average annual specific incidence was highest in the Vysočina, South Bohemian and Olomouc Regions. A total of 18,693 (71.1%) cases of RVGE were hospitalized, most of them in the age groups 1–4 years (34.7%) and 5–9 years (11.9%). Vaccination data were available for 21,142 individuals with RVGE, of whom 304 (1.4%) were reported as vaccinated. The risk of hospitalization for RVGE was statistically significantly lower (p < 0.001) in vaccinated than in unvaccinated individuals. A total of 27 RVGE outbreaks were reported, with the largest one involving 152 cases. Two hundred and twenty-six cases were classified as imported. Conclusions: After the introduction of RVGE vaccination in the Czech Republic, a reduction in RVGE cases, hospitalizations, and deaths was expected. However, a significant impact of vaccination on the RVGE burden has not yet been observed in the country. The main reason continues to be low RVGE vaccine coverage. We therefore recommend including this voluntary vaccination in the schedule covered by health insurance and also call for early communication of the appropriateness of such vaccination between the paediatric/adolescent medicine practitioners and children’s parents.

Cíl práce: Hodnocení pacientů zařazených do registru biologické/cílené léčby BIOREP v České republice za rok 2024. Metody: Bylo provedeno retrospektivní hodnocení pacientů k datu 31. 12. 2024 zařazených do registru BIOREP s diagnózou psoriázy, hidradenitis suppurativa a atopické dermatitidy léčených biologickou/cílenou léčbou v daném období. V případě kategoriálních proměnných byly výsledky vyjádřeny pomocí počtu a procenta. Spojité proměnné byly popsány pomocí počtu, průměru, směrodatné odchylky, mediánu, minima a maxima. Výsledky: K 31. 12. 2024 bylo v registru BIOREP evidováno celkem 8 189 pacientů. S psoriázou bylo sledováno 5 453 pacientů (66,6 %), s hidradenitidou 670 pacientů (8,2 %), 2 020 pacientů (24,7 %) s atopickou dermatitidou a zbývajících 46 pacientů (0,6 %) s použitím „off-label“ léčby. Ve skupině léčených pro psoriázu bylo 62,6 % mužů, průměrný věk pacientů ke konci roku 2024 byl 52,4 let, průměrný věk v době diagnózy byl 25,8 let a při nasazení první biologické/cílené léčby 46,3 let. Průměrná doba od diagnózy do zahájení první cílené léčby byla 20,5 let. Ke konci roku 2024 byli pacienti léčeni cílenou léčbou v průměru 5,4 let. Přidružená onemocnění mělo 70,2 % pacientů, nejčastější byla metabolická/ endokrinní onemocnění (39,4 %) a kardiovaskulární onemocnění (37,1 %). Ze sledovaných komorbidit byla nejčetnější hypertenze (34,4 %), dyslipidémie (26,6 %) a diabetes mellitus (12,5 %). Celkem 75,8 % pacientů trpělo nadváhou či obezitou a v registru bylo 32,9 % kuřáků. Souběžnou psoriatickou artritidu mělo 29,5 % pacientů. Při zahájení léčby a při poslední návštěvě bylo průměrné PASI 18,5 resp. 1,6, BSA bylo v průměru 28,8 % resp. 2,3 % a průměrné DLQI 16,0 resp. 1,5. Po 12 měsících léčby dosáhlo PASI50 celkem 90,9 % pacientů, PASI75 82,4 % pacientů, PASI90 65,3 % pacientů a PASI100 42,2 % pacientů. V roce 2024 nově zahájilo léčbu celkem 578 pacientů, na konci sledovaného roku 2024 bylo aktivně léčeno celkem 4 671 pacientů a nejčastěji používanými preparáty byly Skyrizi (17,2 %), Cosentyx (10,4 %), Kyntheum (9,9 %), Tremfya (9,2 %), Humira (8,9 %) a Taltz (8,4 %). S diagnózou hidradenitis suppurativa bylo v registru na konci sledovaného období celkem 670 pacientů, z toho 54,9 % mužů, průměrný věk byl 44,4 let. V době diagnózy bylo pacientům v průměru 32,2 let a v době nasazení léčby v průměru 41,4 let. Průměrná doba od diagnózy do zahájení první biologické léčby byla 9,1 let a pacienti byli léčeni v průměru 2,9 let. V roce 2024 svou první biologickou léčbu zahájilo celkem 121 pacientů. Na konci sledovaného roku bylo léčeno celkem 507 pacientů, průměrná délka léčby jedním léčivým přípravkem byla 2,4 let a nejčastěji použitým preparátem byla Humira (50,7 %). S atopickou dermatitidou bylo v registru BIOREP sledováno k 31. 12. 2024 celkem 2 020 pacientů, z toho 50 % mužů. V roce 2024 byl průměrný věk pacientů 36,3 let. V době diagnózy onemocnění byl průměrný věk pacientů 5,6 let a při nasazení první cílené léčby 34,7 let. Průměrná doba od diagnózy do zahájení první cílené léčby byla 29,1 let. Ke konci roku 2024 byli pacienti léčeni v průměru 2 roky. Souběžnou alergickou rýmu mělo 57,6 % pacientů, potravinovou alergii 51,9 % a alergické astma 38,5 %. Oční postižení se vyskytlo u 20,5 % pacientů, nejčastější byla atopická konjunktivitida (11,1 %). Průměrné EASI při zahájení léčby a na poslední návštěvě bylo 30,1 resp. 4,0, BSA bylo v průměru 55,8 %, resp. 8,6 % a průměrné DLQI 18,2 resp. 3,8. V roce 2024 zahájilo cílenou léčbu celkem 572 pacientů. Na konci sledovaného roku bylo léčeno celkem 1 820 pacientů, nejvíce pacientů bylo léčeno přípravkem Dupixent (69,5 %) a průměrná délka léčby jedním léčivým přípravkem byla 1,8 let. Závěr: BIOREP je prvním registrem pacientů biologické léčby psoriázy v zemích střední a východní Evropy. Analýza potvrzuje vysokou aktivitu sledovaných onemocnění dle objektivního hodnocení a značné negativní ovlivnění kvality života pacientů při zahájení cílené léčby s poklesem hodnocených parametrů při léčbě. Současně prokazuje významnou prevalenci souběžných onemocnění a rizikových faktorů a dlouhé období nedostatečné léčby před nasazením cílené léčby.

Background and objectives: Evaluation of patients included in the registry of biological/targeted therapy BIOREP in the Czech Republic. Methods: A retrospective evaluation of patients to date 31 December 2024 enrolled in the BIOREP registry was performed. The aim of our study was to evaluate patients on biological/targeted treatment in the given period in individual categories and to analyze the population of patients with psoriasis, hidradenitis suppurativa and atopic dermatitis. In the case of categorical variables, the results were expressed using number and percentage. Continuous variables were described using count, mean, standard deviation, median, minimum, and maximum. Results: As of December 31, 2024, the BIOREP registry included a total of 8,189 patients. Of these, 5,453 (66.6%) were monitored for psoriasis, 670 (8.2%) for hidradenitis suppurativa, 2,020 (24.7%) for atopic dermatitis, and the remaining 46 (0.6%) received “off-label” treatment. Among patients treated for psoriasis, 62.6% were male. The average patient age at the end of 2024 was 52.4 years, the mean age at the time of diagnosis was 25.8 years and 46.3 years at initiation of the first biological/targeted therapy. The average time from diagnosis to initiation of the first targeted therapy was 20.5 years. By the end of 2024, patients had been treated with targeted therapy for an average of 5.4 years. Comorbidities were present in 70.2% of patients, with the most common being metabolic/endocrine disorders (39.4%) and cardiovascular diseases (37.1%). Among the observed comorbidities, the most frequent were hypertension (34.4%), dyslipidemia (26.6%), and diabetes mellitus (12.5%). A total of 75.8% of patients were overweight or obese, and 32.9% were smokers. Psoriatic arthritis was observed in 29.5% of patients. At therapy initiation and the last visit, the mean PASI was 18.5 and 1.6, respectively, BSA was 28.8% and 2.3%, respectively, and DLQI was 16.0 and 1.5, respectively. After 12 months of treatment, a total of 90.9%; 82.4%; 65.3% and 42.2% of patients achieved PASI50, PASI75, PASI90 and PASI100, respectively. In 2024, a total of 578 patients newly initiated treatment, and at the end of the year, 4,671 patients were actively treated. The most commonly used medications were Skyrizi (17.2%), Cosentyx (10.4%), Kyntheum (9.9%), Tremfya (9.2%), Humira (8.9%) and Taltz (8.4%). For hidradenitis suppurativa, the registry included 670 patients at the end of the observation period, with an average age of 44.4 years and 54.9% were male. The average age at diagnosis was 32.2 years, and at treatment initiation, it was 41.4 years. The average time from diagnosis to initiation of the first biological therapy was 9.1 years, and patients had been treated for an average of 2.9 years. In 2024, a total of 121 patients initiated their first biological therapy. By the end of the year, a total of 507 patients were being treated, with an average duration of treatment per medication of 2.4 years. The most commonly used medication was Humira (50.7%). For atopic dermatitis, a total of 2,020 patients were monitored in the BIOREP registry as of December 31, 2024, with 50% being male. The average age of patients in 2024 was 36.3 years. At the time of diagnosis, the average age was 5.6 years, and at the initiation of the first targeted therapy, it was 34.7 years. The average time from diagnosis to the start of the first targeted therapy was 29.1 years. By the end of 2024, patients had been treated for an average of 2 years. Concomitant allergic rhinitis was present in 57.6% of patients, food allergy in 51.9%, and allergic asthma in 38.5%. Ocular comorbidities occurred in 20.5% of patients, the most common were atopic conjunctivitis (11.1%). The mean EASI at treatment initiation and the last visit was 30.1 and 4.0, respectively; BSA was 55.8% and 8.6%, respectively, and DLQI was 18.2 and 3.8, respectively. In 2024, 572 patients initiated targeted therapy. By the end of the year, 1,820 patients were being treated, and the average duration of treatment was 1.8 years, the most common medication was Dupixent (69.5%). Conclusion: BIOREP is the first registry of patients with psoriasis treated with biologics in Central and Eastern Europe. The analysis confirmed the high activity of diseases according to objective evaluation and the significant negative impact on the quality of life before initiation of targeted treatment, with a decrease in the evaluated scores during treatment. Additionally, the analysis highlights the significant prevalence of comorbidities and risk factors, as well as a long diseases duration before the introduction of targeted treatment.

• MeSH
• atopická dermatitida diagnóza   komplikace   terapie   MeSH
• biologická terapie * MeSH
• cílená molekulární terapie MeSH
• hidradenitis suppurativa diagnóza   farmakoterapie   komplikace   MeSH
• komorbidita MeSH
• psoriáza diagnóza   komplikace   terapie   MeSH
• registrace MeSH
• retrospektivní studie MeSH
• Geografické názvy
• Česká republika MeSH

BACKGROUND: Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation of type I interferon (IFN) signalling, we identified a cohort of individuals heterozygous for mutations in PTPN1, encoding the protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe the clinical phenotype and molecular and cellular pathology of this new disease. METHODS: In this case series, we identified patients and collected clinical and neuroradiological data through collaboration with paediatric neurology and clinical genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, and the UK) and Israel. Variants in PTPN1 were identified by exome and directed Sanger sequencing. The expression of IFN-stimulated genes was determined by quantitative (q) PCR or NanoString technology. Experiments to assess RNA and protein expression and to investigate type 1 IFN signalling were undertaken in patient fibroblasts, hTERT-immortalised BJ-5ta fibroblasts, and RPE-1 cells using CRISPR-Cas9 editing and standard cell biology techniques. FINDINGS: Between Dec 20, 2013, and Jan 11, 2023, we identified 12 patients from 11 families who were heterozygous for mutations in PTPN1. We found ten novel or very rare variants in PTPN1 (frequency on gnomAD version 4.1.0 of <1·25 × 10:sup>-6). Six variants were predicted as STOP mutations, two involved canonical splice-site nucleotides, and two were missense substitutions. In three patients, the variant occurred de novo, whereas in nine affected individuals, the variant was inherited from an asymptomatic parent. The clinical phenotype was characterised by the subacute onset (age range 1-8 years) of loss of motor and language skills in the absence of seizures after initially normal development, leading to spastic dystonia and bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) or high T2 white matter signal. Neopterin in CSF was elevated in all ten patients who were tested, and all probands demonstrated an upregulation of IFN-stimulated genes in whole blood. Although clinical stabilisation and neuroradiological improvement was seen in both treated and untreated patients, in six of eight treated patients, high-dose corticosteroids were judged clinically to result in an improvement in neurological status. Of the four asymptomatic parents tested, IFN signalling in blood was normal (three patients) or minimally elevated (one patient). Analysis of patient blood and fibroblasts showed that tested PTPN1 variants led to reduced levels of PTPN1 mRNA and PTP1B protein, and in-vitro assays demonstrated that loss of PTP1B function was associated with impaired negative regulation of type 1 IFN signalling. INTERPRETATION: PTPN1 haploinsufficiency causes a type 1 IFN-driven autoinflammatory encephalopathy. Notably, some patients demonstrated stabilisation, and even recovery, of neurological function in the absence of treatment, whereas in others, the disease appeared to be responsive to immune suppression. Prospective studies are needed to investigate the safety and efficacy of specific immune suppression approaches in this disease population. FUNDING: The UK Medical Research Council, the European Research Council, and the Agence Nationale de la Recherche.

• MeSH
• dítě MeSH
• haploinsuficience * genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mutace genetika   MeSH
• nemoci mozku genetika   MeSH
• neurozánětlivé nemoci genetika   MeSH
• předškolní dítě MeSH
• tyrosinfosfatasa nereceptorového typu 1 * genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The selection of proper reference genes and materials is critical in the design of PCR experiments, especially for differential expression studies. In this study, we propose a method to identify robust endogenous control miRNAs in the visceral adipose tissue of C57BL/6J mice with non-alcoholic fatty liver disease induced by alternating Western and control diets. This study outlines a comprehensive methodology for the analysis of microRNA endogenous controls using microfluidic cards in conjunction with miRNA profiling through small RNA sequencing and subsequent validation by quantitative PCR and the RefFinder algorithm. Criteria included were fold change, p-value, reads per million, and gene stability assessment. A set of six putative endogenous microRNAs was identified (miR-331-3p, let-7a-5p, miR-1839-5p, miR-151a-5p, let-7d-5p, and let-7c-5p). Subsequent validation and analysis using the RefFinder algorithm assessed the stability of the selected genes, and a combination of the three most stable endogenous miRNA controls (miR-331-3p, let-7a- 5p, and miR-1839-5p) exhibiting consistent expression patterns with minimal variability was set. Given the absence of universal endogenous controls, individual evaluation of normalizers for each experiment is imperative for accurate miRNA expression measurements. This approach, which combines multiple techniques and assessments, provides a reliable strategy for identifying and validating endogenous controls in miRNA studies.

• MeSH
• algoritmy MeSH
• mikro RNA * genetika   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nealkoholová steatóza jater * genetika   metabolismus   patologie   MeSH
• nitrobřišní tuk * metabolismus   MeSH
• regulace genové exprese MeSH
• stanovení celkové genové exprese metody   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH