Kolorektální karcinom patří mezi nejčastější nádorová onemocnění s významným podílem metastatických případů. Systémová léčba metastatického kolorektálního karcinomu (mCRC) je dnes určována na základě molekulárního profilu nádoru, který zahrnuje stav mikrosatelitové nestability (MSI), mutační status genů KRAS, NRAS, BRAF a HER2. U pacientů s MSI/dMMR je preferována imunoterapie, zatímco u mikrosatelitově stabilních (MSS) forem závisí léčebná sekvence na přítomnosti mutací KRAS, BRAF a expresi HER2. Standardní terapeutické možnosti zahrnují kombinaci chemoterapie s cílenou terapií (anti-EGFR, antiangiogenní léčba) a novější přístupy, včetně inhibitorů KRAS G12C nebo HER2 cílené terapie. Lokální metody, jako jsou chirurgické resekce a ablační techniky, mohou významně přispět k dlouhodobému přežití. Správná volba léčby v kontextu multidisciplinárního přístupu je klíčová pro optimalizaci výsledků pacientů s mCRC.

Colorectal cancer is one of the most common malignancies, with a significant proportion of metastatic cases. The systemic treatment of metastatic colorectal cancer (mCRC) is now guided by the tumor's molecular profile, including microsatellite instability (MSI) status, mutational status of KRAS, NRAS, BRAF, and HER2 expression. Patients with MSI/dMMR benefit from immunotherapy, while treatment sequencing for microsatellite-stable (MSS) tumors depends on the presence of KRAS, BRAF mutations, and HER2 overexpression. Standard therapeutic options include chemotherapy combined with targeted therapy (anti-EGFR, antiangiogenic agents) and novel approaches such as KRAS G12C inhibitors or HER2-targeted treatments. Local therapies, including surgical resections and ablative techniques, can significantly improve long-term survival. The proper selection of treatment within a multidisciplinary approach is essential for optimizing outcomes in mCRC patients.

• MeSH
• cílená molekulární terapie MeSH
• kolorektální nádory * patologie   terapie   MeSH
• lidé MeSH
• mikrosatelitní nestabilita MeSH
• mutace MeSH
• protinádorové látky imunologicky aktivní farmakologie   terapeutické užití   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protokoly protinádorové léčby MeSH
• Check Tag
• lidé MeSH

Poznatky o molekulárních subtypech karcinomu endometria vedly v posledních několika letech k velkým změnám v klasifikačních systémech, prognostických skupinách a ve svém důsledku v terapeutických postupech u pacientek s pokročilým/metastazujícím karcinomem endometria. Z pohledu imunoterapeutického lze skupinu karcinomů endometria dělit na mikrosatelitově nestabilní (microsatellite instability-high, MSI-H) a skupinu mikrosatelitově stabilní (microsatellite stability, MSS). Mikrosatelitově nestabilní skupina tumorů zpravidla dobře reaguje na monoterapii checkpoint inhibitory, naopak skupina MSS obvykle vyžaduje k dosažení onkologického úspěchu kombinovanou terapii. Nejvýznamnějším posunem v obtížně léčitelné kohortě pacientek s pokročilým a metastazujícím karcinomem endometria od dob konvenční chemoterapie je jednoznačně kombinace pembrolizumabu s lenvatinibem, nezávislá na přítomnosti MSI-H nádorových buněk. Ve skupině MSI-H karcinomů se jako velmi úspěšná kombinace jeví podání dostarlimabu v monoterapii.

Knowledge of the molecular subtypes of endometrial cancer has led to major changes in classification systems, prognostic groups and, consequently, therapeutic procedures for patients with advanced/metastatic endometrial cancer in the last few years. From the point of view of immunotherapy, the group of endometrial cancers can be divided into microsatellite unstable (microsatellite instability-high, MSI-H) and microsatellite stable (microsatellite stability, MSS). The MSI-H tumor group usually responds well to monotherapy with checkpoint inhibitors, whereas the MSS group usually requires combined therapy to achieve oncological success. The most significant shift in the difficult-to-treat cohort of patients with advanced and metastatic endometrial cancer since the days of conventional chemotherapy is clearly the combination of pembrolizumab with lenvatinib, independent of the presence of microsatellite instability of tumor cells. In the group of MSI-H carcinomas, the administration of dostarlimab in monotherapy appears to be a very successful combination.

• Klíčová slova
• dMMR/MSI-H karcinom,
• MeSH
• děložní krvácení MeSH
• imunoterapie * MeSH
• inhibitory kontrolních bodů MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• nádory endometria * chirurgie   diagnóza   epidemiologie   klasifikace   MeSH
• postmenopauza MeSH
• protinádorové látky MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The current knowledge about the immunohistochemical features of adult granulosa cell tumor (AGCT) is mostly limited to the "traditional" immunohistochemical markers of sex cord differentiation, such as inhibin, calretinin, FOXL2, SF1, and CD99. Knowledge about the immunohistochemical markers possibly used for predictive purpose is limited. In our study, we focused on the immunohistochemical examination of 290 cases of AGCT classified based on strict diagnostic criteria, including molecular testing. The antibodies used included 12 of the "diagnostic" antibodies already examined in previous studies, 10 antibodies whose expression has not yet been examined in AGCT, and 7 antibodies with possible predictive significance, including the expression of HER2, PD-L1, CTLA4, and 4 mismatch repair (MMR) proteins. The results of our study showed expression of FOXL2, SF1, CD99, inhibin A, calretinin, ER, PR, AR, CKAE1/3, and CAIX in 98%, 100%, 90%, 78%, 45%, 41%, 94%, 82%, 26%, and 9% of AGCT, respectively. GATA3, SATB2, napsin A, MUC4, TTF1, and CD44 were all negative. PTEN showed a loss of expression in 71% of cases and DPC4 in 4% of cases. The aberrant staining pattern (overexpression) of p53 was found in 1% (3/268) of cases, 2 primary tumors, and 1 recurrent case. Concerning the predictive markers, the results of our study showed that AGCT is microsatellite stable, do not express PD-L1, and are HER2 negative. The CTLA4 expression was found in almost 70% of AGCT tumor cells.

• MeSH
• dospělí MeSH
• imunohistochemie * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádor z folikulárních buněk * patologie   metabolismus   MeSH
• nádorové biomarkery * analýza   MeSH
• nádory vaječníků * patologie   metabolismus   diagnóza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Stage II colon cancer (CC) encompasses a heterogeneous group of patients with diverse survival experiences: 87% to 58% 5-year relative survival rates for stages IIA and IIC, respectively. While stage IIA patients are usually spared the adjuvant chemotherapy, some of them relapse and may benefit from it; thus, their timely identification is crucial. Current gene expression signatures did not specifically target this group nor did they find their place in clinical practice. Since processes at invasion front have also been linked to tumor progression, we hypothesize that aside from bulk tumor features, focusing on the invasion front may provide additional clues for this stratification. A retrospective matched case-control collection of 39 stage IIA microsatellite-stable (MSS) untreated CCs was analyzed to identify prognostic gene expression-based signatures. The endpoint was defined as relapse within 5 years vs. no relapse for at least 6 years. From the same tumors, three different classifiers (bulk tumor, invasion front, and constrained baseline on bulk tumor) were developed and their performance estimated. The baseline classifier, while the weakest, was validated in two independent data sets. The best performing signature was based on invasion front profiles [area under the receiver operating curve (AUC) = 0.931 (0.815-1.0)] and contained genes associated with KRAS pathway activation, apical junction complex, and heme metabolism. Its combination with bulk tumor classifier further improved the accuracy of the predictions.

• Publikační typ
• časopisecké články MeSH

Imunoterapie má v léčbě metastazujícího kolorektálního karcinomu své pevné místo u pacientů s mikrosatelitovou instabilitou/ deficiencí v mismatch repair genech tvořících zhruba 5 % všech metastatických kolorektálních karcinomů. Data z menších studií také silně svědčí pro obdobně dobrou účinnost také u tumorů s mutací POLE1/POLD1. Probíhá intenzivní výzkum snažící se prolomit rezistenci k imunoterapii pozorovanou u mikrosatelitně stabilních nádorů kolorekta. Některé menší nerandomizované studie naznačují možný benefit kombinace imunoterapie s multikinázovými inhibitory nebo chemoterapií a cílenou léčbou v populaci mikrosatelitně stabilních tumorů, avšak negativní výsledky několika nedávno publikovaných studií ukazují nutnost dalšího výzkumu před uvedením do praxe. Slibné se jeví testování nové generace imunoterapie.

Immunotherapy has a established role in the treatment of metastatic colorectal cancer in patients with microsatellite instability/deficiency in mismatch repair genes accounting for roughly 5% of all metastatic colorectal cancers. Data from smaller studies also strongly support similarly good efficacy in tumors with the POLE1/POLD1 mutation. Intensive research is underway to break down the resistance to immunotherapy observed in microsatellite stable colorectal cancers. Some smaller non-randomized studies suggest a possible benefit of combining immunotherapy with multikinase inhibitors or chemotherapy and targeted treatment in the population of microsatellite stable tumors, but negative results from several recently published studies indicate the need for further research before implementation into clinical praxis. Promising results were seen with novel generation of immunotherapy agents.

• MeSH
• biologická terapie metody   MeSH
• cílená molekulární terapie metody   MeSH
• imunoterapie metody   MeSH
• klinická studie jako téma MeSH
• kolorektální nádory * diagnóza   farmakoterapie   patologie   MeSH
• lidé MeSH
• mikrosatelitní nestabilita MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Přehledové sdělení sumarizuje výsledky klinických studií provedených u pacientek s pokročilými stadii karcinomu endometria. Nová léčiva u endometriálního karcinomu navazují na konvenční chemoterapii a patří do léčebného armamentária pokročilých, metastatických a recidivujících stadií onemocnění, která mají dosud špatnou prognózu. Časná stadia jsou obvykle řešena chirurgickým výkonem (event. v kombinaci s adjuvantní radioterapií a/nebo chemoterapií založenou na platině). Karcinom endometria je vhodným kandidátem pro imunoonkoterapii pro častou přítomnost hypermutovaných subtypů buněk (tzv. subtypy dMMR/MSI-H). Novinkami v systémové léčbě pokročilých a recidivujících stadií jsou monoklonální protilátky (lenvatinib, trastuzumab), checkpoint inhibitory (dostarlimab, pembrolizumab) a cílená léčiva (zejména ze skupiny kinázových inhibitorů). V klinické praxi se u gynekologických malignit potvrdila malá účinnost imunoonkoterapeutik v monoterapii, obvykle se kombinují s konvenční chemoterapií nebo s cílenými léčivy. Výjimku představuje právě hypermutovaný dMMR/MSI-H karcinom endometria, v jehož léčbě byly popsány významné výsledky při podávání dostarlimabu v monoterapii. V kombinované terapii bylo nejlepších výsledků dosaženo podáváním antiangiogenního léku lenvatinibu a checkpoint inhibitoru pembrolizumabu, nezávisle na mutačním stavu buněk karcinomu. Významnost úspěchů těchto terapeutik dokládá i recentní změna v doporučených postupech České onkologické společnosti.

The aim of this review article is to summarize updated results of clinical trials of all types of cancer immunotherapy (monoclonal antibodies, antibodydrug conjugates, immune checkpoint inhibitors) and targeted therapy in advanced, metastatic and recurrent endometrial carcinoma, and to discuss current applications and future perspectives. Early stages of endometrial carcinoma can be successfully treated by surgery alone or surgery with adjuvant radiotherapy and chemotherapy. Endometrial cancer is associated with high rates of the microsatellite instabilityhigh condition and DNA mismatch repair deficiency (dMMR/MSIH). Checkpoint inhibition alone has been effective in dMMR/MSIH endometrial carcinoma using dostarlimab. More recently the combination of pembrolizumab and lenvatinib in advanced and recurrent endometrial carcinoma has shown profound response even in MSS (microsatellite stable) subtypes. These results are reflected in updated guidelines of the Czech Society for Oncology.

• Publikační typ
• souhrny MeSH

Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4−82.6), 88.1% (95%-CI, 85.7−90.4), 93.4% (95%-CI, 91.1−95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18−0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17−0.50); p < 0.0001) of the patient’s gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01−0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered.

• Publikační typ
• časopisecké články MeSH

BACKGROUND: Integration of multi-omics data can provide a more complex view of the biological system consisting of different interconnected molecular components, the crucial aspect for developing novel personalised therapeutic strategies for complex diseases. Various tools have been developed to integrate multi-omics data. However, an efficient multi-omics framework for regulatory network inference at the genome level that incorporates prior knowledge is still to emerge. RESULTS: We present IntOMICS, an efficient integrative framework based on Bayesian networks. IntOMICS systematically analyses gene expression, DNA methylation, copy number variation and biological prior knowledge to infer regulatory networks. IntOMICS complements the missing biological prior knowledge by so-called empirical biological knowledge, estimated from the available experimental data. Regulatory networks derived from IntOMICS provide deeper insights into the complex flow of genetic information on top of the increasing accuracy trend compared to a published algorithm designed exclusively for gene expression data. The ability to capture relevant crosstalks between multi-omics modalities is verified using known associations in microsatellite stable/instable colon cancer samples. Additionally, IntOMICS performance is compared with two algorithms for multi-omics regulatory network inference that can also incorporate prior knowledge in the inference framework. IntOMICS is also applied to detect potential predictive biomarkers in microsatellite stable stage III colon cancer samples. CONCLUSIONS: We provide IntOMICS, a framework for multi-omics data integration using a novel approach to biological knowledge discovery. IntOMICS is a powerful resource for exploratory systems biology and can provide valuable insights into the complex mechanisms of biological processes that have a vital role in personalised medicine.

• MeSH
• algoritmy MeSH
• Bayesova věta MeSH
• genové regulační sítě MeSH
• lidé MeSH
• nádory tračníku * MeSH
• systémová biologie metody   MeSH
• variabilita počtu kopií segmentů DNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.

• MeSH
• fixace tkání * MeSH
• fixativa MeSH
• formaldehyd MeSH
• imunohistochemie * MeSH
• kolorektální nádory chemie   genetika   patologie   MeSH
• laboratorní automatizace MeSH
• lidé MeSH
• mikrosatelitní nestabilita * MeSH
• mutace * MeSH
• mutační analýza DNA * MeSH
• nádorové biomarkery * analýza   genetika   MeSH
• prediktivní hodnota testů MeSH
• reprodukovatelnost výsledků MeSH
• zalévání tkání do parafínu * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• srovnávací studie MeSH