Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

• MeSH
• dítě MeSH
• dospělí MeSH
• fibrosarkom * genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   MeSH
• nádorové biomarkery genetika   analýza   MeSH
• nádory měkkých tkání * genetika   MeSH
• nádory z pojivové a měkké tkáně * MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• receptor trkA genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Here, we present newly derived in vitro model for modeling Duchenne muscular dystrophy. Our new cell line was derived by reprogramming of peripheral blood mononuclear cells (isolated from blood from pediatric patient) with Sendai virus encoding Yamanaka factors. Derived iPS cells are capable to differentiate in vitro into three germ layers as verified by immunocytochemistry. When differentiated in special medium, our iPSc formed spontaneously beating cardiomyocytes. As cardiomyopathy is the main clinical complication in patients with Duchenne muscular dystrophy, the cell line bearing the dystrophin gene mutation might be of interest to the research community.

• MeSH
• buněčná diferenciace MeSH
• buněčné linie MeSH
• dítě MeSH
• Duchennova muskulární dystrofie * MeSH
• indukované pluripotentní kmenové buňky * MeSH
• leukocyty mononukleární MeSH
• lidé MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Východiská: Inhibítory imunitných kontrolných bodov (ICI) blokujúce signálnu dráhu proteínu 1 programovanej smrti (PD-1), dramaticky zlepšili prežívanie pacientov s pokročilým nemalobunkovým karcinómom pľúc (NSCLC). Imunohistochemická analýza expresie ligandu 1 programovanej smrti (PD-L1) je toho času najviac využívaným a klinicky validovaným biomarkerom predikujúcim efektívnosť ICI u pacientov s NSCLC, ale sám o sebe predstavuje nedokonalý nástroj. Signálna dráha PD-1 je poprepájaná s početnými celulárnymi ako aj molekulárnymi faktormi prítomnými v nádorovom mikroprostredí (TME) v NSCLC. Celulárne faktory, ktoré sa podieľajú na regulácii expresie PD-L1 v NSCLC sú pripisované aktivite nádor infiltrujúcich lymfocytov a s nádorom asociovanými fibroblastmi. Vnútorné molekulárne faktory, ktoré majú vplyv na úroveň expresie PD-L1 v NSCLC, sú asociované s prítomnosťou onkogénnych driver mutácií v génoch receptora epidermálneho rastového faktora a v homológu virového onkogénu Kirsten rat sarcoma a s translokáciami vedúcimi k prestavbe kinázy anaplastického lymfómu. Okrem toho, na úroveň expresie PD-L1 v NSCLC môže mať vplyv aj stimulácia hypoxických signálnych dráh a aktivácia transformujúceho rastového faktora beta 1. Hlbšie pochopenie zložitých mechanizmov regulujúcich expresiu PD-L1 je nevyhnutné, aby bolo v budúcnosti možné ušiť na mieru terapiu s použitím ICI u pacientov s pokročilým NSCLC. Cieľ: V predkladanom prehľadovom článku prezentujeme súhrn kľúčových faktorov podieľajúcich sa na regulácii expresie PD-L1 v rámci TME v NSCLC, ktoré sú a potenciálne môžu byť využívané za účelom zlepšenia účinnosti imunoterapie, ktorá blokuje signálnu dráhu PD-1.

Background: Immune checkpoint inhibitors (ICI) targeting the programmed cell death protein 1 (PD-1) signaling pathway have dramatically improved the clinical outcomes of oncological patients having advanced non-small cell lung carcinoma (NSCLC). The immunohistochemical analysis of programmed death-ligand 1 (PD-L1) expression remains the most widely used and clinically validated biomarker predicting efficacy of ICI in NSCLC patients, but it represents in isolation an imperfect tool. The PD-1 axis is intricately coupled with numerous cellular and molecular factors within the tumor microenvironment (TME) of NSCLC. Cellular factors implicated in the regulation process of PD-L1 expression in NSCLC are related to the activity of tumor infiltrating lymphocytes and cancer associated fibroblasts. Intrinsic molecular factors which affect the level of PD-L1 expression are associated with the presence of oncogenic driver mutations in the Kirsten rat sarcoma viral oncogene homolog and epidermal growth factor receptor genes and to rearrangements in the anaplastic lymphoma kinase. Furthermore, activation of hypoxic signaling pathways and the transforming growth factor beta 1 axis can have an impact on the level of PD-L1 expression in NSCLC. A deeper understanding of the complex mechanisms regulating PD-L1 expression is necessary to tailor the treatment with ICI in patients with advanced NSCLC. Purpose: In this review, we present an overview of key factors underlying the regulation of PD-L1 expression within the TME of NSCLC, which are, and potentially can be, exploited to improve the outcomes of immunotherapy targeting the PD-1 axis.

• MeSH
• antigeny CD274 MeSH
• antigeny CD279 MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• nádory plic farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND: Transformation of EGFR (epidermal growth factor receptor) - mutant non-small cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) is one mechanism of resistance to tyrosine kinase inhibitor (TKI) treatment, seen in approximately 3-10% cases. Such transformed SCLC often retains the original EGFR mutation (EGFRM), which is not otherwise observed in SCLC. CASE REPORT: We present a 67 y/o woman with pulmonary adenocarcinoma (AC) and EGFRM deletion on exon 19. After initial treatment with whole brain radiotherapy and 7 months of TKI afatinib, progression was observed. Liquid biopsy detected deletion on exon 19 and T790M mutation. Chemotherapy carboplatin plus pemetrexed was administered, with no response. Genetics from a rebiopsy of lung revealed deletion on exon 19. After 12 months treatment with TKI osimertinib, a progression in lung and pancreas lesions was detected, docetaxel was used, with followig progression. The lung biopsy revealed SCLC. Significant elevation of serum markers carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) was observed at the time of the SCLC diagnosis. Treatment with carboplatin and etoposide was not effective. The next biopsy found two populations of cells: SCLC and AC. The biopsy from the pancreatic lesion revealed metastasis of SCLC. PCR confirmed EGFRM deletion on exon 19 in the lung SCLC tissue sample. The following treatment lines of topotecan, erlotinib were not effective. The patient survived 36 months from diagnosis, 7 months from detection of SCLC. CONCLUSION: Screening for transformation of EGFR-mutant NSCLC to SCLC should be considered in resistance to TKI. In the presented case, this rare transformation was confirmed by histopathologic examination and by PCR. EGFRM in the lung SCLC, identical to that found in the original lung AC, was detected. Further, the observed elevation of serum tumor markers NSE and CEA can indicate this infrequent transformation and help to decide on rebiopsy.

• MeSH
• adenokarcinom plic * genetika   farmakoterapie   MeSH
• chemorezistence genetika   MeSH
• erbB receptory genetika   terapeutické užití   MeSH
• inhibitory proteinkinas MeSH
• karboplatina terapeutické užití   MeSH
• karcinoembryonální antigen genetika   terapeutické užití   MeSH
• lidé MeSH
• malobuněčný karcinom plic * genetika   farmakoterapie   patologie   MeSH
• mutace MeSH
• nádory plic * farmakoterapie   genetika   patologie   MeSH
• nemalobuněčný karcinom plic * genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

We present here a new iPS cell line for modeling sporadic form of ALS. Cell line was generated by reprogramming skin fibroblasts isolated with explant culture technology from skin biopsy, donated by ALS patient. For reprogramming, polycistronic self-replicating RNA vector was used and derived iPS cells were characterized by immunocytochemistry and FACS (pluripotent factors expression), karyotyping, STR fingerprinting analysis and in vitro differentiation assay. New cell line showed normal (46, XY) karyotype and differentiated in vitro into cells from three germ layers. STR analysis proved the origin and originality of the cell line.

• MeSH
• amyotrofická laterální skleróza * patologie   MeSH
• buněčná diferenciace MeSH
• buněčné linie MeSH
• fibroblasty metabolismus   MeSH
• indukované pluripotentní kmenové buňky * metabolismus   MeSH
• lidé MeSH
• technologie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Objev indukované pluripotence v roce 2006 umožnil revoluční způsob získávaní autologních terapeuticky aplikovatelných buněk, a mož‐ nost modelovat jakékoliv onemocnění v in vitro podmínkách. Možnost vrátit libovolnou, finálně diferencovanou buňku „v čase“ zpátky do stádia pluripotence je zajímavé i pro oblast onkologického výzkumu. Tato technologie umožnila studium procesů spojených s roz‐ vojem nádorového fenotypu buňky a taky s přechodem nádorové buňky do stádia s nižší mírou diferenciace. Reprogramování buněk do indukovaných pluripotentních kmenových buněk také pomáhá mnohem lépe studovat raritní populaci buněk, přítomných v nádo‐ rech – tzv. nádorové kmenové buňky. Indukovaná pluripotence některých typů nádorových buněk, spojená s jejich následnou řízenou diferenciací by se zároveň mohla stát jednou z možných terapeutických aplikací v onkologii.

Discovery of technology of induced pluripotency that allows the generation of autologous therapeutically applicable cells and generati‐ on of in vitro cell models for diseases with limited (or highly invasive) access to tested cells has also opened new horizons in the field of oncology research. The unique ability to reprogram the cancer cell into pluripotency with subsequent directed differentiation into cell with no malignant phenotype should be considered as a challenge in the field of new oncotherapy development. Although still conside‐ red to be realistic only on the level of experimental approach, the recent progress in the field of induced pluripotency gives the hope that dedifferentiation‐based therapies connected with the erase of malignant phenotype of original cancer cell will be more realistic in near future. By then, the most important role of induced pluripotency in oncology remains in the field of regenerative therapy as a source of autologous cells for regeneration of tissues or organs damaged by tumor growth or aggressive therapy

• MeSH
• lidé MeSH
• nádorové kmenové buňky MeSH
• nádory terapie   MeSH
• přeprogramování buněk MeSH
• techniky buněčného přeprogramování * metody   MeSH
• Check Tag
• lidé MeSH

Gastrointestinálne stromálne tumory (GISTy) predstavujú najčastejšie mezenchýmové nádory tráviaceho traktu. Ich súčasná liečba dnes, v závislosti od viacerých parametrov ochorenia, zahŕňa najmä chirurgickú resekciu a biologickú liečbu inhibítormi tyrozínových kináz (TKIs). Tu prezentujeme raritný prípad 53-ročného pacienta s mutáciou p.W557_558Kdel exónu 11 c-KIT génu v primárnom GISTe žalúdka diagnostikovanom v gastroskopickej biopsii, ktorý bol liečený neoadjuvantnou cielenou liečbou imatinibom. Po počiatočnej fáze stabilizácie ochorenia vznikla u pacienta rezistencia na túto terapiu. Napriek liečbe TKI inhibítormi druhej a tretej línie a totálnej chirurgickej extirpácii v ďalšom priebehu dochádzalo k opakovaným remisiám a relapsom. V resekčnom materiáli sme identifikovali viacpočetné mutácie v rôznych exónoch c-KIT génu, kde pri perzistencii primárnej delečnej mutácie v exóne 11 vznikli ďalšie sekundárne zriedkavé mutácie v exónoch 13 (p.V654A) a 17 (p.Y823D). Opakované úseky remisií a relapsov tak po liečbe TKIs, ako aj po chirurgickej resekcii tumoru, poukazujú na nepriaznivý vplyv týchto genetických zmien a otvárajú otázku potreby modifikácie terapeutického prístupu imatinib-rezistentných GISTov striedaním jednotlivých TKIs namiesto doteraz zaužívanej monoterapie.

Gastrointestinal stromal tumours (GISTs) represent the most common mesenchymal tumours of the digestive tract. Based on various parameters, the recent GIST treatment includes surgical and/or targeted therapy using tyrosine kinase inhibitors (TKIs). In this paper we present a case of 53-year-old patient with c-KIT exon 11 (p.W557_558Kdel) mutated primary GIST of stomach diagnosed by a gastroscopic biopsy and treated by neoadjuvant TKI therapy using imatinib. After incipient disease stabilization, the patient developed therapy resistance. In spite of the second and third-line TKI treatment and radical surgery, the following disease course consisted of repeated remissions and relapses. The resection material showed multiple c-KIT mutations in various exons, including persisting primary exon 11 deletion mutation and two secondary infrequent c-KIT mutations in exon 13 (p.V654A) and exon 17 (p.Y823D). Repeating cycles of remissions and relapses after TKI treatments and surgical resection show the adverse effects of these genetic mutations on GIST behaviour and might advocate therapy management modification allowing therapeutic combinations of TKIs instead of conventional monotherapies in imatinib resistent GISTs.

• MeSH
• axony patologie   MeSH
• biologická terapie metody   MeSH
• chemorezistence MeSH
• cílená molekulární terapie metody   MeSH
• gastrointestinální stromální tumory * chirurgie   farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezenchymom chirurgie   farmakoterapie   MeSH
• mutace MeSH
• neoadjuvantní terapie metody   MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny c-kit * genetika   MeSH
• stomatochirurgické výkony MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Erdheimova-Chesterova choroba (ECD) patrí medzi malígne polyostotické sklerotické formy non-Langerhansovej histiocytózy. Pri abnormálnej proliferácii patologických histiocytov „penovitých buniek“ napadnuté štruktúry hypertrofujú, zvyšujú svoju denzitu, objavuje sa jazvenie. Choroba postihuje najmä diafýzy a metafýzy dlhých kostí dolných končatín s typickým prejavom bolesti. Podľa WHO je choroba klasifikovaná ako histiocytózna neoplázia. Referujeme o 74-ročnej pacientke s expanzívnym ložiskom v oblasti horného klivu a sfenoidálnej kosti vpravo. Histologické vyšetrenie potvrdilo túto zriedkavú chorobu, ktorou trpí asi len 600 pacientov na svete.

Erdheim-Chester disease (ECD) belongs to the malignant polyostotic sclerotic forms of non-Langerhans histiocytosis. During abnormal prolipheration of pathologic histiocytes (foam cells), involved structures become hypertrophic with increased density followed by scarring. Mostly the diaphysis and metaphysis of long bones of lower limbs with typical pain are involved. According to the WHO, the disease is classified as histiocytic neoplasia. We refer on a 74-year-old female patient with expansive process in the region of upper clivus and sphenoidal bone on the right side. Histological testing confirmed this very rare disease that affects about 600 patients over the world.

• MeSH
• diferenciální diagnóza MeSH
• Erdheimova-Chesterova nemoc * diagnóza   terapie   MeSH
• histiocyty patologie   účinky záření   MeSH
• lidé MeSH
• nádory hlavy a krku diagnostické zobrazování   radioterapie   MeSH
• senioři MeSH
• vzácné nemoci MeSH
• zadní jáma lební * diagnostické zobrazování   patologie   účinky záření   MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Single nucleotide polymorphisms can create a genetic microenvironment in some tumors that affects the course of treatment, resistance, etc. Whether single nucleotide polymorphisms have an impact on gastrointestinal stromal tumor (GIST) development and disease progression is not yet accurately verified. KIT SNPM541L in exon 10 correlates with a worse prognosis of many cancers. The impact of KIT SNPM541L in GISTs is relatively unknown and, therefore, its analyses could have potential in patient therapy and could provide more detailed information on tumor character, clinical presentation, or tumor behavior in treatment. AIM: The aim of the study was the analysis of the biological and clinical significance of the KIT SNPM541L polymorphism in exon 10. MATERIALS AND METHODS: Paraffin sample tissues were obtained from the National GIST Register in Martin. Retrospective samples from 177 GIST patients were divided into several groups. Detection of SNPM541L was performed by Sanger sequencing. Statisitical analyses were performed to determine the prevalence of KIT SNPM541L in the Slovak GIST cohort, to search for correlation between c-KIT status and clinicopathological, molecular and biological data. RESULTS: Overall, 29 samples out of 177 showed KIT SNPM541L polymorphism. CONCLUSION: Our results do not support the association between KIT SNPM541L and increased risk of relapse in localized primary GISTs. Additionally, we found a positive correlation between KIT SNPM541L occurrence and earlier onset of relapse in PDGFRa and WT subgroup of GISTs.

• MeSH
• dospělí MeSH
• gastrointestinální nádory epidemiologie   genetika   patologie   MeSH
• gastrointestinální stromální tumory epidemiologie   genetika   patologie   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• následné studie MeSH
• prognóza MeSH
• protoonkogenní proteiny c-kit genetika   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

AIMS: Coronavirus disease 2019 is responsible for a worldwide increase in morbidity and mortality. The relationship of this infection to mother-to-child vertical transmission has not been elucidated yet. However, recent reports indicate a foetal death rate of up to 3%. METHODS: We report a case of sudden pre-term foetal demise in a woman positive for SARS-CoV-2 but asymptomatic, with physiological course of pregnancy. RESULTS: One of the possible explanations of sudden foetal death may be acute placental insufficiency caused by a SARS-CoV-2 placental infection or the development of foetal inflammatory response syndrome (FIRS). CONCLUSION: Considering the potential risk of foetal demise, questions remain regarding foetal monitoring and the timing of labour and delivery in the second and third trimesters, particularly in asymptomatic or mild maternal SARS-CoV-2 infection. A relevant multidisciplinary team must also be aware of these risks associated with possibly fatal consequences.

• MeSH
• COVID-19 virologie   MeSH
• dospělí MeSH
• infekční komplikace v těhotenství virologie   MeSH
• lidé MeSH
• odumření plodu * MeSH
• placenta virologie   MeSH
• SARS-CoV-2 izolace a purifikace   MeSH
• těhotenství MeSH
• vertikální přenos infekce MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH