Uroteliální karcinom (UC) představuje závažný onkologický problém s vysokou mortalitou, zejména u pokročilých stadií. Adjuvantní terapie, ať už chemoterapie, nebo imunoterapie, hraje klíčovou roli ve snižování rizika relapsu a zlepšení přežití po radikální operaci. Tento přehled shrnuje současné poznatky o využití adjuvantní léčby u UC a uroteliálního karcinomu horních cest močových (UTUC), včetně jeho histologických variant. Nejlépe etablovanou modalitou je chemoterapie na bázi cisplatiny, která prokázala přínos zejména u pacientů s vysokým rizikem relapsu (pT3-4, N+) bez předchozí neoadjuvantní chemoterapie. Významný průlom přinesla imunoterapie, zejména nivolumab, jehož účinnost byla potvrzena v randomizované studii CheckMate 274, přičemž největší benefit byl pozorován u pacientů s vysokou expresí PD-L1. Problematické zůstává postavení adjuvantní terapie u histologických variant UC, kde je potřeba dalšího výzkumu. Budoucí směřování adjuvantní léčby zahrnuje identifikaci prediktivních biomarkerů, včetně ctDNA, a vývoj personalizovaných strategií, které zohlední molekulární a imunitní charakteristiky nádoru. Optimalizace selekce pacientů pomocí tekutých biopsií a dalších biomarkerů je klíčem ke zlepšení dlouhodobých výsledků.

Urothelial carcinoma (UC) represents a significant oncological challenge with high mortality, particularly in advanced stages. Adjuvant therapy, whether chemotherapy or immunotherapy, plays a crucial role in reducing the risk of relapse and improving survival after radical surgery. This review summarises current knowledge on the use of adjuvant treatment in UC and upper tract urothelial carcinoma (UTUC), including its histological variants. The most established modality remains cisplatin-based chemotherapy, which has demonstrated benefits, particularly in patients at high risk of relapse (pT3-4, N+) without prior neoadjuvant chemotherapy. A major breakthrough has been the introduction of immunotherapy, especially nivolumab, whose efficacy was confirmed in the randomised CheckMate 274 trial, with the most significant be­nefit observed in patients with high PD-L1 expression. The role of adjuvant therapy in histological variants of UC remains unclear and requires further research. The future direction of adjuvant treatment involves the identification of predictive biomarkers, including circulating tumour DNA (ctDNA) and developing personalised strategies that consider the molecular and immune characteristics of the tumour. Optimising patient selection using liquid biopsies and other biomarkers is key to improving long-term outcomes.

Terapie bispecifickými protilátkami se v hematoonkologii dostává do popředí zájmu, a to zejména u B lymfoproliferací. Jedná se o léčbu využívající imunitní systém pacienta k eliminaci nádorových buněk. Epkoritamab je podkožně podávaná anti-CD20/CD3 bispecifická protilátka, která prokázala významnou účinnost v léčbě relabujících nemocných s difuzním velkobuněčným B lymfomem po selhání dvou a více linií léčby. Na základě výsledků registrační studie fáze 1b/2 EPCORE NHL-1 byla prokázána léčebná odpověď u 63,1 % pacientů, z toho 38,9 % dosáhlo kompletní remise. Medián doby do dosažení kompletní remise byl 2,7 měsíce. Medián doby do progrese onemocnění byl 4,4 měsíce. Toxicita léku je přijatelná, dobře predikovatelná a při dodržení preventivních opatření není při podávání léku problémem. Epkoritamab je podáván do progrese nemoci a/nebo toxicity. Epkoritamab je aktuálně registrován v USA a EU, v rámci České republiky je očekávána úhrada pro nemocné po dvou a více předchozích liniích léčby na přelomu roku 2024/2025. Do budoucna bude zajímavé sledovat, zda se lék posune do časnějších linií léčby difuzního velkobuněčného B lymfomu nemocných - je nutno vyčkat výsledků klinických studií, které v této oblasti probíhají, a to i v celé řadě center v České republice. Zkušenosti, které jsme dosud nabyli s tímto lékem v rámci klinických studií, jsou velmi slibné.

Therapy with bispecific antibodies is gaining prominence in hemato-oncology, particularly in B-lymphoproliferative disorders. This treatment utilizes the patient’s immune system to eliminate cancer cells. Epcoritamab is a subcutaneously administered anti-CD20/CD3 bispecific antibody that has demonstrated significant efficacy in treating relapsed patients with diffuse large B-cell lymphoma after the failure of two or more lines of therapy. Based on the results of the phase 1b/2 registration trial, EPCORE NHL-1, a therapeutic response was observed in 63.1% of patients, with 38.9% achieving complete remission. The median time to complete remission was 2.7 months. The median time to progression was 4.4 months. The drug’s toxicity is acceptable, well predictable, and, with proper preventive measures, is not a challenge during administration. Epcoritamab is administered until disease progression and/or toxicity. It is currently approved in the USA and the EU, and in the Czech Republic, reimbursement for patients after two or more prior lines of therapy is expected around the turn of the year 2024/2025. In the future, it will be interesting to see if the drug moves into earlier lines of treatment for diffuse large B-cell lymphoma patients, though the results of ongoing clinical trials, including those at many centers in the Czech Republic, will need to be awaited. The experience we have gained so far with this drug in clinical trials is very promising.

Chronická zápalová demyelinizačná polyneuropatia (CIDP) je získaná, imunitne sprostredkovaná neuropatia, spôsobená zápalom periférnych nervov a nervových koreňov. Jedná sa o najčastejšiu chronickú autoimunitnú polyneuropatiu, ktorá je stále poddiagnostikovaným ochorením. Ak sa dlhodobo nelieči alebo je liečená nesprávne, môže viesť k závažnému zneschopneniu s narušením jemnej motoriky, chôdze a celkovej mobility pacienta. CIDP býva asociovaná s viacerými ochoreniami ako sú diabetes mellitus, monoklonálne gamapatie, infekcia HIV, malignity či viaceré systémové ochorenia. V poslednej dobe pribúda referencií, že prevalencia CIDP má tendenciu byť vyššia u diabetikov, najmä u pacientov vo vyššom veku. Diagnostika CIDP u pacienta s diabetom je náročná, pretože superponované axonálne poškodenie pri možnej diabetickej neuropatii môže zakryť typické demyelinizačné elektrofyziologické nálezy. Na druhej strane diabetická polyneuropatia môže spôsobiť zvýšenie hladiny proteínov v likvore. Vo vysvetlení asociácie týchto dvoch ochorení existuje stále viacero kontroverzií. Stále nemáme adekvátny diagnostický nástroj pre jasné definovanie CIDP u diabetika. Výzvou pre neurológov je práve identifikácia potenciálnych biomarkerov CIDP u diabetického pacienta, pretože CIDP je liečiteľné ochorenie.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated neuropathy caused by inflammation of peripheral nerves and nerve roots. It is the most common chronic autoimmune polyneuropathy, which is still considered underdiagnosed. If it remains untreated or improperly treated for a long time, it can lead to severe disability with impairment of the patient‘s fine motor skills, walking, and general mobility. CIDP may be associated with several diseases such as diabetes mellitus, monoclonal gammopathy, HIV infection, malignancies, or several systemic diseases. Recently, there have been several references that the prevalence of CIDP tends to be higher in diabetics, especially in older patients. Diagnosing CIDP in a patient with diabetes is challenging, because superimposed axonal damage in possible diabetic neuropathy can obscure typical demyelinating electrophysiological findings. On the other hand, diabetic polyneuropathy can cause elevated protein in cerebrospinal fluid. There are still many controversies in explaining the association of these two diseases. We still do not have an adequate diagnostic tool to clearly define CIDP in diabetic patients. The identifying a potential biomarkers of CIDP in diabetic patients is a challenge for neurologists, as CIDP is a treatable disease.

• MeSH
• Biomarkers MeSH
• Polyradiculoneuropathy, Chronic Inflammatory Demyelinating * diagnosis   therapy   MeSH
• Diabetes Mellitus, Type 2 complications   MeSH
• Diabetic Neuropathies diagnosis   MeSH
• Diagnosis, Differential MeSH
• Electromyography MeSH
• Diabetes Complications MeSH
• Middle Aged MeSH
• Humans MeSH
• Gait Disorders, Neurologic diagnosis   etiology   therapy   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH
• Review MeSH

The rising burden of fungal infections presents a significant challenge to global healthcare, particularly with increasing antifungal resistance limiting treatment efficacy. Early detection and timely intervention remain critical, yet fungal pathogens employ diverse mechanisms to evade host immunity and develop resistance, undermining existing therapeutic options. Limited antifungal options and rising resistance necessitate novel treatment strategies. This review provides a comprehensive overview of conventional antifungal agents, their mechanisms of action, and emerging resistance pathways. Furthermore, it highlights recently approved and investigational antifungal compounds while evaluating innovative approaches such as nanotechnology, drug repurposing, and immunotherapy. Addressing antifungal resistance requires a multifaceted strategy that integrates novel therapeutics, enhanced diagnostic tools, and future research efforts to develop sustainable and effective treatment solutions.

• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: The pathophysiology of sepsis-induced acute kidney injury remains elusive. Although mitochondrial dysfunction is often perceived as the main culprit, data from preclinical models yielded conflicting results so far. The aim of this study was to assess the immune-metabolic background of sepsis-associated renal dysfunction using sequential biopsy approach with mitochondria function evaluation in a large clinically relevant porcine models mimicking two different paces and severity of sepsis and couple this approach with traditional parameters of renal physiology. METHODS: In this randomized, open-label study, 15 anaesthetized, mechanically ventilated and instrumented (renal artery flow probe and renal vein catheter) pigs were randomized in two disease severity groups-low severity (LS) sepsis (0.5 g/kg of autologous faeces intraperitoneally) and high severity (HS) sepsis (1 g/kg of autologous faeces intraperitoneally). Sequential cortical biopsies of the left kidney were performed and a pyramid-shaped kidney specimen with cortex, medulla and renal papilla was resected and processed at the end of the experiment. Oxygraphic data and western blot analysis of proteins involved in mitochondrial biogenesis and degradation were obtained. RESULTS: In contrast to increased mitochondrial activity observed in LS sepsis, a significant decrease in the oxidative phosphorylation capacity together with an increase in the respiratory system uncoupling was observed during the first 24 h after sepsis induction in the HS group. Those changes preceded alterations of renal haemodynamics. Furthermore, serum creatinine rose significantly during the first 24 h, indicating that renal dysfunction is not primarily driven by haemodynamic changes. Compared to cortex, renal medulla had significantly lower oxidative phosphorylation capacity and electron-transport system activity. PGC-1-alfa, a marker of mitochondrial biogenesis, was significantly decreased in HS group. CONCLUSIONS: In this experimental model, unique sequential tissue data show that the nature and dynamics of renal mitochondrial responses to sepsis are profoundly determined by the severity of infectious challenge and resulting magnitude of inflammatory insult. High disease severity is associated with early and stepwise progression of mitochondria dysfunction and acute kidney injury, both occurring independently from later renal macro-haemodynamic alterations. Our data may help explain the conflicting results of preclinical studies and suggest that sepsis encompasses a very broad spectrum of sepsis-induced acute kidney injury endotypes.

• Publication type
• Journal Article MeSH

Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. Ex vivo T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients. We investigated 20 T-lymphocytopenic patients, including 13 patients awaiting first-line treatment and 7 patients with failed immune reconstitution after previous HCT or thymus transplantation. Whilst developmental blocks in ex vivo T-lymphopoiesis indicated hematopoietic cell-intrinsic defects, successful T-lymphocyte differentiation required careful interpretation, in conjunction with clinical status, immunophenotyping, and genetic investigations. Of the 20 patients, 13 proceeded to treatment, with successful immune reconstitution observed in 4 of the 6 patients post-HCT and 4 of the 7 patients after thymus transplantation, the latter including two patients who had previously undergone HCT. Whilst further validation and standardization are required, we conclude that assessing ex vivo T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.

• MeSH
• Cell Differentiation MeSH
• Child MeSH
• Immunophenotyping MeSH
• Infant MeSH
• Humans MeSH
• Lymphopenia * immunology   MeSH
• Lymphopoiesis * genetics   MeSH
• Adolescent MeSH
• Child, Preschool MeSH
• Primary Immunodeficiency Diseases therapy   genetics   immunology   MeSH
• T-Lymphocytes * immunology   MeSH
• Thymus Gland immunology   MeSH
• Hematopoietic Stem Cell Transplantation * methods   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Cellular senescence precipitates a decline in physiological activities and metabolic functions, often accompanied by heightened inflammatory responses, diminished immune function, and impaired tissue and organ performance. Despite extensive research, the mechanisms underpinning cellular senescence remain incompletely elucidated. Emerging evidence implicates circadian rhythm and hypoxia as pivotal factors in cellular senescence. Circadian proteins are central to the molecular mechanism governing circadian rhythm, which regulates homeostasis throughout the body. These proteins mediate responses to hypoxic stress and influence the progression of cellular senescence, with protein Brain and muscle arnt-like 1 (BMAL1 or Arntl) playing a prominent role. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of oxygen homeostasis within the cellular microenvironment, orchestrates the transcription of genes involved in various physiological processes. HIF-1α not only impacts normal circadian rhythm functions but also can induce or inhibit cellular senescence. Notably, HIF-1α may aberrantly interact with BMAL1, forming the HIF-1α-BMAL1 heterodimer, which can instigate multiple physiological dysfunctions. This heterodimer is hypothesized to modulate cellular senescence by affecting the molecular mechanism of circadian rhythm and hypoxia signaling pathways. In this review, we elucidate the intricate relationships among circadian rhythm, hypoxia, and cellular senescence. We synthesize diverse evidence to discuss their underlying mechanisms and identify novel therapeutic targets to address cellular senescence. Additionally, we discuss current challenges and suggest potential directions for future research. This work aims to deepen our understanding of the interplay between circadian rhythm, hypoxia, and cellular senescence, ultimately facilitating the development of therapeutic strategies for aging and related diseases.

• MeSH
• Molecular Targeted Therapy MeSH
• Circadian Rhythm * physiology   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit metabolism   MeSH
• Cell Hypoxia MeSH
• Hypoxia metabolism   physiopathology   MeSH
• Humans MeSH
• Signal Transduction MeSH
• Cellular Senescence * MeSH
• ARNTL Transcription Factors metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Accumulating evidence suggests that spontaneous preterm labor is a syndrome caused by multiple pathological processes. The breakdown of maternal-fetal tolerance has been proposed as a key mechanism of idiopathic spontaneous preterm labor, often viewed as a chronic inflammatory process resulting from the maternal immune system's impaired tolerance of the fetus from early pregnancy. Regulatory T cells are crucial for maintaining maternal-fetal tolerance. Even a partial reduction in their levels can disrupt this tolerance, leading to adverse pregnancy outcomes such as preterm labor. Given the complexity of the T lymphocyte-mediated immune response, identifying candidate signaling pathways involved in maternal-fetal tolerance is challenging. However, current literature highlights the importance of the functional and developmental markers FoxP3, CD45RA, Helios, and CD39 due to their immunosuppressive abilities essential for maintaining pregnancy. OBJECTIVE: This study aimed to determine whether changes in numbers of selected regulatory T cell subpopulations in the first trimester are associated with subsequent spontaneous preterm labor. STUDY DESIGN: This prospective study enrolled 43 women with early singleton pregnancies, excluding those with autoimmune diseases, diabetes mellitus (type 1, type 2), primary hypertension, or who had been treated with vaginal progesterone prior to sample collection. We analyzed regulatory T cell subpopulations in maternal circulation using the DURAClone IM T cell kit, focusing on the following subsets: CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-. RESULTS: Among the participants, 7 experienced spontaneous preterm labor between the 23rd and 33rd weeks of gestation, while 36 delivered at term. The preterm group showed a significant reduction in numbers of all analyzed regulatory T cell subpopulations: CD4+CD25+FoxP3+ (median 0.0410×10ˆ9/L vs median 0.0550×10ˆ9/L, P=.0217), CD4+CD25+FoxP3+CD45RA- (median 0.0310×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0216), CD4+CD25+FoxP3+Helios+ (median 0.0270×10ˆ9/L vs median 0.0370×10ˆ9/L, P=.0260), CD4+CD25+FoxP3+CD39- (median 0.0300×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0427). CONCLUSION: Early first trimester alterations in specific regulatory T cell subpopulations, including diminished levels of CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA-, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-, are associated with idiopathic spontaneous preterm labor. These findings suggest that early changes in these lymphocyte subpopulations may be linked to spontaneous preterm birth. This highlights the need for further research to understand the mechanisms underlying regulatory T-cell dynamics and their impact on pregnancy outcomes.

• MeSH
• Leukocyte Common Antigens metabolism   MeSH
• Apyrase immunology   MeSH
• Antigens, CD immunology   MeSH
• Adult MeSH
• Forkhead Transcription Factors * metabolism   MeSH
• Humans MeSH
• Young Adult MeSH
• Obstetric Labor, Premature * immunology   MeSH
• Prospective Studies MeSH
• Pregnancy Trimester, First immunology   MeSH
• T-Lymphocytes, Regulatory * immunology   MeSH
• Pregnancy MeSH
• Ikaros Transcription Factor MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Cathelicidins are a group of cationic, amphipathic peptides that play a vital role in the innate immune response of many vertebrates, including humans. Produced by immune and epithelial cells, they serve as natural defenses against a wide range of pathogens, including bacteria, viruses, and fungi. In humans, the cathelicidin LL-37 is essential for wound healing, maintaining skin barrier integrity, and combating infections. Cathelicidins of different origins have shown potential in treating various skin conditions, including melanoma, acne, and diabetic foot ulcers. Despite their promising therapeutic potential, cathelicidins face significant challenges in clinical application. Many peptide-based therapies have failed in clinical trials due to unclear efficacy and safety concerns. Additionally, the emergence of bacterial resistance, which contradicts initial claims of non-resistance, further complicates their development. To successfully translate cathelicidins into effective clinical treatments, therefore, several obstacles must be addressed, including a better understanding of their mechanisms of action, sustainable large-scale production, optimized formulations for drug delivery and stability, and strategies to overcome microbial resistance. This review examines the current knowledge of cathelicidins and their therapeutic applications and discusses the challenges that hinder their clinical use and must be overcome to fully exploit their potential in medicine.

• Publication type
• Journal Article MeSH
• Review MeSH

This report delves into the challenges and potential solutions associated with flexible, customized subcutaneous immunoglobulin (SCIG) infusion regimens for patients with primary antibody deficiency disease (PAD). Advances in the treatment of inborn errors of immunity, particularly PAD, have converted fatal diseases into chronic, complex, long-term conditions that make adherence to treatment a critical issue. Conventional SCIG infusion regimens, while clinically effective, may not always align with the varied lifestyles, changing lifestyles and commitments of patients which can lead to missed doses, diminishing adherence thus posing potential health risks and compromising the overall effectiveness of treatment. For these reasons, it's important to develop flexible infusion regimens tailored to meet individual patient needs. Patient-centric strategies that promote shared decision-making and awareness of patient status not only promote medical efficacy but also enhance the overall patient experience. The authors of this report call attention for a need to shift toward more adaptable and individualized SCIG treatment plans for PAD patients whose needs may change over the long-term course of treatment.

• MeSH
• Immunoglobulins therapeutic use   administration & dosage   MeSH
• Precision Medicine MeSH
• Humans MeSH
• Patient-Centered Care * MeSH
• Primary Immunodeficiency Diseases therapy   immunology   MeSH
• Infusions, Subcutaneous * MeSH
• Immunologic Deficiency Syndromes * therapy   drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH