Přestavba genu RET (též translokace RET) se vyskytuje u 1-2 % případů nemalobuněčného karcinomu plic (non-small cell lung cancer, NSCLC).1 Přítomnost driver mutací receptoru epidermálního růstového faktoru (epidermal growth factor receptor, EGFR) a anaplastické lymfomové kinázy (anaplastic lymphoma kinase, ALK) u NSCLC je spojena se sníženou odpovědí na imunoterapii. Ostatní, méně časté aktivační mutace (KRAS, MET, BRAF a RET) mají méně dat a slabší negativní vazbu, ale i tak není účinnost imunoterapie stejná jako u nemutované populace.2 Pacienti s RET+ NSCLC mají zpravidla nízkou expresi ligandu programované buněčné smrti 1 (programmed cell death-ligand 1, PD-L1) a nízkou mutační nálož, což jsou faktory spojené spíše s nižším účinkem imunoterapie. Prezentujeme případ pacientky s RET+ NSCLC, u které léčba atezolizumabem vedla ke stabilizaci choroby na jeden rok (přestože onkomarkery pomalu, ale vytrvale stoupaly), a tato stabilizace umožnila pacientce přečkat kritické období, kdy nám nebyl dostupný žádný inhibitor RET. Následná léčba pralsetinibem pak měla a má výborný účinek.

RET gene rearrangement (also called RET translocation) occurs in 1-2% of non-small cell lung cancer (NSCLC) cases.1 The presence of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) driver mutations in NSCLC is associated with a reduced response to immunotherapy. Other, less common activating mutations (KRAS, MET, BRAF and RET) have less data and weaker negative association, but even so, the efficacy of immunotherapy is not the same as in the non-mutated population.2 RET+ NSCLC generally have low PD-L1 expression and low mutational load - factors more likely associated with smaller immunotherapy effectiveness. We present the case of a patient with RET+ NSCLC in whom treatment with atezolizumab led to disease stabilization for one year and this disease stabilization allowed the patient to survive a critical period when no RET inhibitor was available yet. Subsequent treatment with pralsetinib then had and continues to have an excellent effect.

Burn management has significantly advanced in the past 75 years, resulting in improved mortality rates. However, there are still over one million burn victims in the United States each year, with over 3,000 burn-related deaths annually. The impacts of individual patient, hospital, and regional demographics on length of stay (LOS) and total cost have yet to be fully explored in a large nationally representative cohort. Thus, this study aimed to examine various hospital and patient characteristics using a sample of over 20,000 patients. Inpatient data from the National Inpatient Sample from 2008 to 2015 were analyzed, and only patients with an ICD-9 code for second- or third-degree burns were included. In addition, a major operating room procedure must have been indicated on the discharge summary for patients to be included in the final dataset, ensuring that only severe burns requiring complex care were analyzed. Analysis of covariance models was used to evaluate the impact of various patient, hospital, and regional variables on both LOS and cost. The study found that skin grafts and fasciotomy significantly increased the cost of hospitalization. Having burns on the face, neck, and trunk significantly increased costs for patients with second-degree burns, while burns on the trunk resulted in the longest LOS for patients with third-degree burns. Infections in the hospital and additional procedures, such as flaps and skin grafts, also led to longer stays. The study also found that the prevalence of postoperative complications, such as electrolyte imbalance, was high among patients with burn surgery.

• MeSH
• délka pobytu MeSH
• fasciotomie MeSH
• hospitalizace MeSH
• lidé MeSH
• popálení * chirurgie   MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Spojené státy americké MeSH

Burn management has significantly advanced in the past 75 years, resulting in improved mortality rates. However, there are still over one million burn victims in the US each year, with over 3,000 burn-related deaths annually. The impacts of individual patient, hospital, and regional demographics on length of stay (LOS) and total cost have yet to be fully explored in a large nationally representative cohort. Thus, this study aimed to examine various hospital and patient characteristics using a sample of over 20,000 patients. Inpatient data from the National Inpatient Sample (NIS) from 2008-2015 was analyzed, and only patients with an ICD-9 code for second or third-degree burns were included. Additionally, a major operating room procedure must have been indicated on the discharge summary for patients to be included in the final dataset, ensuring that only severe burns requiring complex care were analyzed. Analysis of Covariance (ANCOVA) models were used to evaluate the impact of various patient, hospital, and regional variables on both LOS and cost. The study found that skin grafts and fasciotomy significantly increased the cost of hospitalization. Having burns on the face, neck, and trunk significantly increased costs for patients with second-degree burns, while burns on the trunk resulted in the longest LOS for patients with third-degree burns. Infections in the hospital and additional procedures, such as flaps and skin grafts, also led to longer stays. The study also found that the prevalence of post-operative complications, such as electrolyte imbalance, was high among burn surgery patients.

• Publikační typ
• časopisecké články MeSH

Akutní poškození ledvin je velmi častou komplikací u septických pacientů a jeho rozvoj je nezávislým silným prediktorem vysoké úmrtnosti. Původní výklad patogeneze poškození ledvin v sepsi se opíral o renální vazokonstrikci a akutní tubulární nekrózu. Nové poznatky však vzbudily velký zájem o intrarenální inflamaci a mikrovaskulární poruchy, zřejmě klíčové prvky v patofyziologii tohoto syndromu. Přestože v současnosti neexistuje specifická farmakologická léčba septického akutního poškození ledvin, je jeho včasné rozpoznání a komplexní léčba zásadní nejen pro osud ledvin, ale i septických pacientů. Tento článek shrnuje epidemiologii, patofyziologii, diagnostiku a léčebné strategie akutního poškození ledvin v sepsi.

Acute kidney injury is frequently encountered in septic patients and is strong independent predictor of adverse outcomes. Emerging data have led to a resurgence of interest in the importance of intrarenal inflammation and microvascular derangements rather than confining it to renal vasoconstriction and acute tubular necrosis as the primary driver of renal impairment. Although no specific pharmacological interventions are currently available, timely recognition and appropriate management of such patients is vital. This review will summarize epidemiology, pathophysiology, diagnosis and protective and treatment strategies in septic acute kidney injury.

• Klíčová slova
• podpora orgánů, léčba, multiorgánová dysfunkce,
• MeSH
• akutní poškození ledvin diagnóza   komplikace   terapie   MeSH
• antibakteriální látky aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• diuretika škodlivé účinky   terapeutické užití   MeSH
• diuréza fyziologie   imunologie   účinky léků   MeSH
• financování organizované MeSH
• hemodynamika MeSH
• jednotky intenzivní péče normy   využití   MeSH
• klinický obraz nemoci MeSH
• komorbidita MeSH
• kreatinin analýza   izolace a purifikace   krev   MeSH
• lidé MeSH
• medicína založená na důkazech trendy   MeSH
• multiorgánové selhání diagnóza   komplikace   terapie   MeSH
• náhrada funkce ledvin metody   využití   MeSH
• sepse diagnóza   komplikace   terapie   MeSH
• septický šok diagnóza   komplikace   terapie   MeSH
• šok MeSH
• urgentní lékařství metody   trendy   MeSH
• věkové faktory MeSH
• Check Tag
• lidé MeSH

Symptomatické krvácení u mozkových nádorů je vzácné. Zcela raritní je koincidence traumatu a krvácení do tumoru. Uvádíme případ 53letého pacienta, který havaroval jako řidič osobního automobilu. Za 1 hodinu od úrazu byl pacient v hlubokém kómatu (GCS 6) s mydriázou vpravo. Dle CT jsme soudili na kontuzní ložisko parietálně vpravo s intracerebrální hemoragií. Po provedení dekompresivní kraniektomie nad levou hemisférou a zevní komorové drenáži se stav nemocného neměnil. CT a AG vyšetření prokázala, že se jednalo o krvácení do tumoru, který jsme 3. den po úrazu odstranili. Histologicky se jednalo o multiformní glioblastom. O tom, zda v našem případě krvácení bylo způsobeno úrazem, či nehodě předcházelo, lze jen spekulovat.

Symptomatic hemorrhage from a brain tumor is uncommon. The concidence of a trauma and brain tumor hemorrhage is quite rare. A 53-year-old patient had a traffic accident as a car driver. One hour after the injury he was comatose (GCS 6) with mydriasis on the right. According to CT the development of the brain contusion with intracranial hemorrhage in the right parietal region was thought of. The decompressive craniectomy with external ventricular drainage was carried out. CT scan and agiography led to the correct diagnosis – hemorrhage of the malignant tumor origin. The tumor was resected 3 days after the injury. Histological examinations proved multiform glioblastoma. We can only speculate whether the tumor bleeding started spontaneously or after the trauma.

• MeSH
• dopravní nehody MeSH
• glioblastom chirurgie   MeSH
• komorbidita MeSH
• lidé MeSH
• muži MeSH
• traumatické krvácení do mozku radiografie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

The great popularity of various diets in recent years has led us to reflect on their suitability for our health. The aim of this communication is to review current knowledge on the influence of the most well-known diets on the concentrations of the main steroids and to consider possible mechanisms. The influence of diet on hormone concentrations is expected, but the literature data on this topic are inconsistent and yield conflicting results. The main problem in evaluating these influences is the change in weight that a change in diet induces. This effect needs to be filtered out in order to discover interesting associations between diet and steroid hormones. This is illustrated by the example of the effects of ketogenic diets on testosterone levels in men, where the direct effect of the diet is to reduce testosterone levels, but a number of papers have described increases that are due to diet-related weight loss and the modification of obesity-induced changes. A second major driver is the change in circadian rhythm, and it is necessary to assess hormonal changes induced by changing the time of day of the diet. Such shifts within the circadian rhythm rather than due to a particular type of diet itself are documented by changes in the circadian rhythm of cortisol.

• MeSH
• cirkadiánní rytmus MeSH
• dieta * MeSH
• hydrokortison MeSH
• lidé MeSH
• obezita MeSH
• steroidy * krev   MeSH
• testosteron MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

POU3F3 adjacent non-coding transcript 1 (PANTR1) is an oncogenic long non-coding RNA with significant influence on numerous cellular features in different types of cancer. No characterization of its role in renal cell carcinoma (RCC) is yet available. In this study, PANTR1 expression was confined to human brain and kidney tissue and was found significantly up-regulated in clear-cell renal cell carcinoma tissue (ccRCC) compared to non-cancerous kidney tissue in two independent cohorts (p < 0.001 for both cohorts). In uni- and multivariate Cox regression analysis, ccRCC patients with higher levels of PANTR1 showed significantly poorer disease-free survival in our own respective cohort (n = 175, hazard ratio: 4.3, 95% confidence interval: 1.45-12.75, p = 0.008) in accordance with significantly poorer overall survival in a large The Cancer Genome Atlas database (TCGA) cohort (n = 530, hazard ratio: 2.19, 95% confidence interval: 1.59-3.03, p ≤ 0.001). To study the underlying cellular mechanisms mediated by varying levels of PANTR1 in kidney cancer cells, we applied siRNA-mediated knock-down experiments in three independent ccRCC cell lines (RCC-FG, RCC-MF, 769-P). A decrease in PANTR1 levels led to significantly reduced cellular growth through activation of apoptosis in all tested cell lines. Moreover, as angiogenesis is a critical driver in ccRCC pathogenesis, we identified that PANTR1 expression is critical for in vitro tube formation and endothelial cell migration (p < 0.05). On the molecular level, knock-down of PANTR1 led to a decrease in Vascular Endothelial growth factor A (VEGF-A) and cell adhesion molecule laminin subunit gamma-2 (LAMC2) expression, corroborated by a positive correlation in RCC tissue (for VEGF-A R = 0.19, p < 0.0001, for LAMC2 R = 0.13, p = 0.0028). In conclusion, this study provides first evidence that PANTR1 has a relevant role in human RCC by influencing apoptosis and angiogenesis.

• Publikační typ
• časopisecké články MeSH

Spitzoidní nádory představují heterogenní skupinu melanocytárních neoplázií vykazujících široké spektrum biologického chování od zcela benigních afekcí typu névu Spitzové až po maligní léze v podobě spitzoidních melanomů. Mezi těmito dvěma skupinami se pak nacházejí léze s nejistým biologickým chováním v podobě atypických spitzoidních tumorů. Histologicky jsou charakterizované objemnými epiteloidními a/nebo vřetenitými melanocyty uspořádanými do fasciklů nebo hnízd a často s charakteristickou epidermální hyperplázií a fibrovaskulárními stromálními změnami v okolí. Rozpoznání specifických strukturálních přestaveb v genech pro tyrozinkinázové receptory ROS1, ALK, NTRK1, NTRK2, NTRK3, RET, MET, serin threoninové kinázy BRAF a MAP3K8 či HRAS mutací v posledním desetiletí umožnilo přesnější klinickou, morfologickou a molekulární subklasifikaci spitzoidních tumorů. Rozpoznání specifických histologických rysů pak může dermatopatologům napomoct nejen v hodnocení těchto lézí, ale může i nepřímo poukazovat na konkrétní molekulární změny. Tento doškolovací článek se zaměřuje na klinické a morfologické nálezy u molekulárně definovaných podskupin spitzoidních tumorů.

Spitz tumors represent a heterogeneous group of challenging melanocytic neoplasms, displaying a range of biological behaviors, spanning from benign lesions, Spitz nevi (SN) to Spitz melanomas (SM), with intermediate lesions in between known as atypical Spitz tumors (AST). They are histologically characterized by large epithelioid and/or spindled melanocytes arranged in fascicles or nests, often associated with characteristic epidermal hyperplasia and fibrovascular stromal changes. In the last decade, the detection of mutually exclusive structural rearrangements involving receptor tyrosine kinases ROS1, ALK, NTRK1, NTRK2, NTRK3, RET, MET, serine threonine kinases BRAF and MAP3K8, or HRAS mutation, led to a clinical, morphological and molecular based classification of Spitz tumors. The recognition of some reproducible histological features can help dermatopathologist in assessing these lesions and can provide clues to predict the underlying molecular driver. In this review, we will focus on clinical and morphological findings in molecular Spitz tumor subgroups.

• MeSH
• epiteloidní a vřetenobuněčný névus * diagnóza   genetika   klasifikace   patologie   MeSH
• genová přestavba genetika   MeSH
• molekulární patologie klasifikace   metody   MeSH
• nádory kůže klasifikace   patologie   MeSH
• Publikační typ
• přehledy MeSH

The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2-16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression.

• MeSH
• akutní myeloidní leukemie farmakoterapie   genetika   MeSH
• alely MeSH
• dospělí MeSH
• frekvence genu účinky léků   genetika   MeSH
• hydroxymočovina aplikace a dávkování   MeSH
• Janus kinasa 2 genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace účinky léků   genetika   MeSH
• myeloproliferativní poruchy farmakoterapie   genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• progrese nemoci MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The central stalk of mitochondrial ATP synthase consists of subunits γ, δ, and ε, and along with the membraneous subunit c oligomer constitutes the rotor domain of the enzyme. Our previous studies showed that mutation or deficiency of ε subunit markedly decreased the content of ATP synthase, which was otherwise functionaly and structuraly normal. Interestingly, it led to accumulation of subunit c aggregates, suggesting the role of the ε subunit in assembly of individual enzyme domains. In the present study we focused on the role of subunits γ and δ. Using shRNA knockdown in human HEK293 cells, the protein levels of γ and δ were decreased to 30% and 10% of control levels, respectively. The content of the assembled ATP synthase decreased in accordance with the levels of the silenced subunits, which was also the case for most structural subunits. In contrast, the hydrophobic c subunit was increased to 130% or 180%, respectively and most of it was detected as aggregates of 150-400 kDa by 2D PAGE. In addition the IF1 protein was upregulated to 195% and 300% of control levels. Both γ and δ subunits silenced cells displayed decreased ATP synthase function - lowered rate of ADP-stimulated respiration, a two-fold increased sensitivity of respiration to inhibitor oligomycin, and impaired utilization of mitochondrial membrane potential for ADP phosphorylation. In summary, similar phenotype of γ, δ and ε subunit deficiencies suggest uniform requirement for assembled central stalk as driver of the c-oligomer attachment in the assembly process of mammalian ATP synthase.

• MeSH
• genový knockdown MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mitochondriální proteiny genetika   metabolismus   MeSH
• mitochondrie genetika   metabolismus   MeSH
• protonové ATPasy genetika   metabolismus   MeSH
• spotřeba kyslíku fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH