The temporomandibular joint (TMJ) is one of the most used joints in the body. Defects and wear in the cartilage of the joint, condyle, and fibrocartilage disc lie at the heart of many common TMJ disorders. During postnatal development, the condyle acts as a growth center for the mandible, with cells moving as a conveyor belt away from the top of the condyle as they differentiate. The superficial layers of the condyle have been proposed to contain stem/progenitor populations to allow growth and maintain homeostasis. Here we have focused on the role of fibroblast-specific protein 1 (FSP1; also known as S100a4) as a key fibroblast stem/progenitor marker for the condyle. Lineage tracing with FSP1-Cre;R26RmTmG mice revealed that FSP1-expressing cells were restricted to the superficial fibroblast zone, giving rise to all layers of the condyle over time. The FSP1-expressing cells overlapped with other putative stem cell markers of the condyle, such as Gli1 and scleraxis. BrdU pulse chase experiments highlighted that a subset of FSP1 fibrocartilage was label retaining, suggesting that FSP1 labels a novel stem/progenitor cell population in the condyle. Destruction of FSP1-expressing cells by conditional diphtheria toxin activity in FSP1-Cre;R26RDTA mice resulted in severe TMJ osteoarthritis with loss of the cartilage structure. Lgr5-expressing cells in the superficial layer of the condyle have been shown to create a Wnt inhibitory niche. FSP1 expression postnatally was associated with a reduction in canonical Wnt activity in the condyle. Importantly, constitutive activation of Wnt/β catenin in FSP1-expressing cells led to a downregulation of FSP1 and progressive postnatal loss of TMJ condylar hyaline cartilage due to loss of the superficial stem/progenitor cells. These data demonstrate a novel role for FSP1-expressing cells in the superficial zone in growth and maintenance of the TMJ condylar cartilage and highlight the importance of regulating Wnt activity in this population.
- Klíčová slova
- Wnt signaling, condyle, fibrocartilage, osteoarthritis, stem cell, temporomandibular disorders,
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Recently, a plethora of novel systemic agents have been incorporated into the therapeutic armamentarium of advanced urothelial carcinoma (aUC). The antibody-drug conjugate (ADC), enfortumab vedotin (EV), has demonstrated relevant clinical benefit in patients with aUC refractory to platinum and immune-checkpoint inhibitor (ICI) therapy. Our study provides a retrospective, international, real-world analysis comparing the effectiveness of EV to chemotherapy in this setting. METHODS: The data were extracted from the medical records of patients treated with EV or chemotherapy following pembrolizumab for recurrent or progressive aUC after platinum-based chemotherapy. Patients were assessed for overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and duration of response (DoR). RESULTS: Our analysis included 247 patients treated with EV (88, 36%) or chemotherapy (159, 64%). Median OS was 9.1 months (95%CI 7.2-10.7) in the overall study population, 13.6 months (95%CI 10.0-31.0) in patients receiving EV and 6.8 months (95%CI 6.0-8.9) in patients receiving chemotherapy (p < 0.001). The OS benefit of EV was not affected by primary tumour site and histology, metastatic sites, type of first platinum-based chemotherapy or response to pembrolizumab. In the EV cohort, the median PFS was significantly longer (8.8 months [95%CI 6.5-17.0] vs. 3.0 months [95%CI 2.6-3.7]) and the ORR was significantly higher (56% vs. 23%) than in the chemotherapy cohort. CONCLUSIONS: The results of our international analysis of real-world data confirm the effectiveness of EV in the sequential strategy of aUC patients who have received prior platinum-based chemotherapy and anti-PD-1 pembrolizumab, regardless of commonly considered prognostic factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05290038.
- Klíčová slova
- ARON‐2 study, NCT05290038, chemotherapy, enfortumab vedotin, pembrolizumab, real‐world data, sequencing, urothelial carcinoma,
- MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * terapeutické užití aplikace a dávkování MeSH
- inhibitory kontrolních bodů terapeutické užití MeSH
- karcinom z přechodných buněk farmakoterapie mortalita patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití aplikace a dávkování MeSH
- protokoly antitumorózní kombinované chemoterapie * terapeutické užití MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- urologické nádory farmakoterapie patologie mortalita MeSH
- výsledek terapie 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
- multicentrická studie MeSH
- Názvy látek
- enfortumab vedotin MeSH Prohlížeč
- humanizované monoklonální protilátky * MeSH
- inhibitory kontrolních bodů MeSH
- monoklonální protilátky MeSH
- pembrolizumab MeSH Prohlížeč
Precise localization of peripheral nerve injuries and evaluation of their prognosis based on clinical and electrodiagnostic examinations are particularly challenging in the acute phase. High-resolution ultrasound (HRUS) may offer a viable and cost-effective imaging option for assessing the morphology of nerve injuries. Consequently, a systematic review and meta-analysis of studies on the use of ultrasound for diagnosing traumatic nerve injuries were conducted. A total of 15 studies were included, reporting the most recent findings on using HRUS in the diagnosis of traumatic nerve injury. These studies assessed the diagnostic test accuracy of ultrasound for the detection of traumatic nerve injury in 272 participants, with the cross-sectional area at the site of traumatic nerve injury also reported in 1,249 participants. The pooled sensitivity and specificity of the included studies were 92% confidence interval (CI) (0.89-0.95) and 86% CI (0.82-0.89), respectively. The positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 13.76 CI (1.41-134.34), 0.08 CI (0.03-0.18), and 286.23 CI (21.22-3,860.40), respectively. In the summary of the receiver operating characteristic curve, the area under the curve was 0.986, and the Q* index was 0.949. Based on the current literature, HRUS has shown promising results in addition to its availability and feasibility. HRUS can serve as a valuable complement to clinical and electrodiagnostic examinations for diagnosing traumatic peripheral nerve injuries. Further research is recommended to better understand the ultrasound characteristics of these injuries.
- MeSH
- lidé MeSH
- poranění periferního nervu * diagnostické zobrazování diagnóza MeSH
- ultrasonografie * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
INTRODUCTION: The main goal of this study was to describe the Czech population of patients with MG in terms of demographics, disease characteristics, management approaches, and treatment trends. METHODS: We selected all patients, both incident and prevalent, who were enrolled in the Czech MyReg registry between August 24, 2015 and November 19, 2021. For the descriptive analysis, all patients enrolled in the registry, regardless of their date of diagnosis or date of enrolment, were included. We analyzed the following disease-related endpoints: myasthenia gravis composite (MGC) score, forced vital capacity (FVC), and Myasthenia Gravis Foundation of America (MGFA) clinical classification. RESULTS: The incidence showed a consistent increasing trend from 0.62 to 3.13. The mean MGC score was 5.0 (median 4.0, 95% CI 4.7, 5.3) representing mild form of MG. The difference in FVC from the predicted value in patients during and without myasthenic crisis was 58.93% (95% CI 37.27, 80.59) and 75.93% (95% CI 74.87, 77.00), respectively. We identified 70 patients (5.0%) with refractory MG, of whom 58.6% were female. The MGFA classifications in those with refractory vs. non-refractory disease was as follows: IIa 21.8% vs 23.2%, IIb 45.3% vs 33.6%, and IIIb 14.1% vs 4.6%, respectively. CONCLUSION: Our analysis shows that the incidence of MG is increasing in the Czech Republic and that patients with refractory disease, of whom up to 58% are female, have a higher burden of disease than non-refractory patients.
- Klíčová slova
- Burden of disease, FVC, MGC score, MGQoL15, Myasthenia gravis, Refractory patients,
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The definition of minor ischemic stroke (MIS) is a topic of debate, however, the most accepted definition is a stroke with National Institutes of Health Stroke Scale (NIHSS) ≤ 5. Intravenous thrombolysis (IVT) is a crucial treatment option for acute ischemic stroke (AIS) including: alteplase, recombinant human tissue-type plasminogen activator (r-tPA), and the recently approved tenecteplase. However, there is a debate regarding its safety and efficacy. Therefore, our objective was to determine the safety and efficacy of IVT in treating minor stroke patients (NIHSS ≤ 5). METHODS: Using the search strategy assigned which was based on three keywords: "mild" or "minor", "stroke", and "intravenous thrombolysis", we searched for eligible articles on PubMed, Web of Science, Embase, and Scopus from inception till 10th January 2024. We conducted this meta-analysis using the random effect model to account for the heterogeneity among the studies. For the dichotomous variables, we calculated the odds ratio (OR) from the event and total of these variables. While for the continuous variables, we calculated the mean difference (MD) of these variables. Pooling of OR for the occurrence of events was also conducted. RESULTS: A total of 21 articles with 93,057 patients with MIS were included. The mean age of the participants ranged from 62.3 to 79.6. Most of the included patients had comorbidities such as hypertension, diabetes, previous stroke, smoking, atrial fibrillation, and hyperlipidemia. Of these, 10,850 received IVT while 82,207 did not. The use of IVT was statistically significant associated with 90-day modified Rankin score (mRs) 0-1 when compared with control with OR of 1.67 (95%CI: 1.46, 1.91, p < 0.00001) and was statistically significantly associated with improvement of NIHSS on discharge with OR of 2.19 (95%CI: 1.56, 3.08, p < 0.00001). In terms of safety outcomes, IVT has proven a safe profile, as there was no significant difference in intracranial hemorrhage (ICH) and mortality rates between the IVT and control groups with OR of 1.75 (95CI: 0.95, 3.23, p = 0.07) and 0.93 (95%CI: 0.77, 1.11, p = 0.41), respectively. CONCLUSION: Although some studies have not found any benefits of IVT in MIS patients, a substantial body of literature strongly endorses IVT as an effective and safe treatment for MIS. IVT has been shown to improve the mRs and NIHSS scores at the 90-day mark without an increased risk of ICH or mortality.
- Klíčová slova
- Acute ischemic stroke, Efficacy, Intracranial hemorrhage, Safety, Tissue Plasminogen Activator,
- MeSH
- cévní mozková příhoda farmakoterapie MeSH
- fibrinolytika * aplikace a dávkování terapeutické užití MeSH
- intravenózní podání MeSH
- ischemická cévní mozková příhoda farmakoterapie MeSH
- lidé MeSH
- tkáňový aktivátor plazminogenu aplikace a dávkování terapeutické užití škodlivé účinky MeSH
- trombolytická terapie * metody MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
- Názvy látek
- fibrinolytika * MeSH
- tkáňový aktivátor plazminogenu MeSH
BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.
- Klíčová slova
- Antitumor immunity, Immune checkpoint inhibitors, Peripheral blood circulating immune subsets, Predictive biomarker,
- MeSH
- antigeny CD278 metabolismus MeSH
- antigeny CD279 antagonisté a inhibitory MeSH
- antigeny CD28 MeSH
- CD8-pozitivní T-lymfocyty imunologie účinky léků metabolismus MeSH
- dospělí MeSH
- inhibitory kontrolních bodů * terapeutické užití farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom * farmakoterapie imunologie krev patologie MeSH
- nádory plic * farmakoterapie imunologie krev patologie MeSH
- nemalobuněčný karcinom plic * farmakoterapie imunologie krev patologie MeSH
- senioři nad 80 let MeSH
- senioři 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
- Názvy látek
- antigeny CD278 MeSH
- antigeny CD279 MeSH
- antigeny CD28 MeSH
- ICOS protein, human MeSH Prohlížeč
- inhibitory kontrolních bodů * MeSH
BACKGROUND: Ring 18 chromosome is a rare chromosomal aberration associated with a wide range of symptoms affecting all organ systems. One possible symptom associated with this condition is an orofacial cleft. However, to date, there are very few reported cases where the cleft has been surgically treated. CASE DESCRIPTION: In our case study, we present a female patient with Ring 18 chromosome who underwent cleft palate surgery at 14 months of age. Subsequently, a reoperation of the palate was necessary due to wound dehiscence. For the secondary reconstruction of the palate, the acellular dermal matrix (ADM) MatriDerm® was used to improve healing. The cleft palate surgery progressively improved her ability to take in food, allowing a transition from nasogastric tube feeding to oral intake. RESULTS: This is only the fourth reported case of a child with Ring 18 chromosome undergoing surgical correction of an orofacial cleft. Additionally, it is one of the first cases where an ADM MatriDerm® was used in the surgical correction of a cleft palate. In this study, we also present a comprehensive literature review, providing an overview of the various symptoms associated with this syndrome. CONCLUSION: Cleft palate surgery had a very positive effect on improving food intake in the patient with Ring 18 chromosome. The use of an acellular dermal matrix during the secondary cleft palate surgery led to improved healing and a good outcome.
- Klíčová slova
- Acellular dermal matrix, Anesthesia in children, Cleft lip and palate, Ring 18 chromosome,
- MeSH
- kojenec MeSH
- kruhové chromozomy * MeSH
- lidé MeSH
- lidské chromozomy, pár 18 genetika MeSH
- rozštěp patra * genetika chirurgie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- přehledy MeSH
BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder with significant clinical implications, including life-threatening myasthenic crises and exacerbations. Understanding real-world treatment patterns, especially associated direct medical costs, is essential for the effective management of healthcare delivery. METHODS: We conducted a descriptive cohort study using health administrative claims data from the Czech Republic covering more than 1,500 prevalent MG patients. Data were analysed for healthcare resource utilization, medication costs, and hospitalization rates related to MG and its complications. RESULTS: Acetylcholine inhibitors and corticosteroids were widely prescribed, with 91.1% and 75.2% of patients receiving them at least once, respectively. Immunosuppressive therapy was given to 45.2% of patients. Myasthenic crises occurred in 2% of patients, with a mean hospitalization cost of 21,020 EUR, while exacerbations occurred in 9.2% of patients, with lower costs (5,951 EUR per hospitalization). Outpatient intravenous immunoglobulin and plasma exchange therapies incurred additional costs of 20,700 EUR and 18,206 EUR per person-year, respectively. The mean total cost per patient-year was 1,271 EUR, with significant cost differences among patients with different treatment patterns. CONCLUSION: This study offers real-world insights into the treatment patterns and associated direct medical costs of MG in the Czech Republic. Myasthenic crises and exacerbations pose considerable cost burdens, while outpatient therapies and common pharmacotherapies are less costly. These findings are vital for healthcare planning, economic evaluation, and resource allocation, potentially leading to enhanced patient care and outcomes.
- Klíčová slova
- Direct healthcare costs, Myasthenia gravis, Treatment patterns,
- MeSH
- dospělí MeSH
- hospitalizace ekonomika MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- myasthenia gravis * ekonomika terapie farmakoterapie MeSH
- náklady na zdravotní péči MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Anaplastic Large Cell Lymphoma (ALCL) is a rare and aggressive T-cell lymphoma, classified into ALK-positive and ALK-negative subtypes, based on the presence of chromosomal translocations involving the ALK gene. The current standard of treatment for ALCL is polychemotherapy, with a high overall survival rate. However, a subset of patients does not respond to or develops resistance to these therapies, posing a serious challenge for clinicians. Recent targeted treatments such as ALK kinase inhibitors and anti-CD30 antibody-drug conjugates have shown promise but, for a fraction of patients, the prognosis is still unsatisfactory. METHODS: We investigated the genetic landscape of ALK + ALCL by whole-exome sequencing; recurring mutations were characterized in vitro and in vivo using transduced ALCL cellular models. RESULTS: Recurrent mutations in FAT family genes and the transcription factor RUNX1T1 were found. These mutations induced changes in ALCL cells morphology, growth, and migration, shedding light on potential factors contributing to treatment resistance. In particular, FAT4 silencing in ALCL cells activated the β-catenin and YAP1 pathways, which play crucial roles in tumor growth, and conferred resistance to chemotherapy. Furthermore, STAT1 and STAT3 were hyper-activated in these cells. Gene expression profiling showed global changes in pathways related to cell adhesion, cytoskeletal organization, and oncogenic signaling. Notably, FAT mutations associated with poor outcome in patients. CONCLUSIONS: These findings provide novel insights into the molecular portrait of ALCL, that could help improve treatment strategies and the prognosis for ALCL patients.
- MeSH
- anaplastický velkobuněčný lymfom * genetika patologie farmakoterapie MeSH
- fenotyp MeSH
- kadheriny * genetika MeSH
- lidé MeSH
- mutace * MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- prognóza MeSH
- sekvenování exomu MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kadheriny * MeSH
