Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.
- MeSH
- Immunotherapy * methods MeSH
- Papillomavirus Infections immunology virology MeSH
- Humans MeSH
- Disease Models, Animal * MeSH
- Mutation * MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Tumor Microenvironment * immunology MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Exome Sequencing MeSH
- Tumor Escape genetics MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Rosette-forming glioneuronal tumors (RGNTs) with FGFR1 tyrosine kinase domain internal tandem duplication (FGFR1 ITD) is exceedingly rare, with only a few cases reported in the literature. Hereby we present a case of a tumor with RGNT morphology occurring in area of septum pellucidum of 43-year-old male. The tumor showed FGFR1 ITD, no PIK3CA, PIK3R1 or NF1 alterations and inconclusive methylation profile with match for class of "low-grade glial/glioneuronal/neuroepithelial tumors". No areas characteristic of dysembryoplastic neuroepithelial tumor were identified. A brief review of literature on discrepancies between morphological diagnosis of RGNT and molecular profile of the entity is provided.
- MeSH
- Adult MeSH
- Humans MeSH
- Brain Neoplasms * pathology genetics MeSH
- Neoplasms, Neuroepithelial * pathology genetics MeSH
- Receptor, Fibroblast Growth Factor, Type 1 * genetics MeSH
- Tandem Repeat Sequences MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
Initiation of newborn screening (NBS) programs in Europe dates back to the 1960s. One of the most recent expansions of NBS programs was the addition of severe combined immunodeficiency (SCID) based on detection of T-cell receptor excision circles (TRECs). In this review, we present an overview of the current situation in Europe. To avoid a biased overview based on only published results, a 37-item survey on TREC-based NBS was sent to representatives of 46 European countries. With a response rate of 83%, we collected data of 38 countries. Seventeen of the 38 European countries that have completed the survey have nationally or regionally implemented TREC-based NBS. The survey results emphasize similarities and differences as well as common practices and challenges in TREC-based NBS. Because TRECs are a general surrogate marker for severe T lymphocytopenia, conditions other than SCID are also identified. Therefore, the initial definition of the target disease as "SCID" might need to be reconsidered and extended to "SCID and severe T lymphocytopenia." Even though complete harmonization of TREC-based NBS programs across Europe will remain challenging, collaboration and close partnerships will help in the move toward universal TREC-based screening for all newborns, resulting in more infants with SCID and severe T lymphocytopenia being detected each year.
- MeSH
- Humans MeSH
- Lymphopenia * immunology diagnosis MeSH
- Infant, Newborn MeSH
- Neonatal Screening * MeSH
- Receptors, Antigen, T-Cell * genetics immunology MeSH
- Severe Combined Immunodeficiency * diagnosis epidemiology immunology MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Geographicals
- Europe MeSH
BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.
- MeSH
- Immunotherapy methods MeSH
- Humans MeSH
- Tumor-Associated Macrophages immunology MeSH
- Tumor Microenvironment * immunology MeSH
- Prostatic Neoplasms * immunology pathology therapy MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Immunotherapy represents a revolutionary advancement in cancer treatment, which has traditionally focused on T cells; however, the role of B cells in cancer immunotherapy has gained interest because of their role in antigen presentation, antibody production, and cytokine release. In this study, we examined the role of B cells in previously developed intratumoral MBTA therapy (mannan-BAM, TLR ligands, and anti-CD40 antibody) in murine models of MTT pheochromocytoma. The results indicated that B cells significantly enhance the success of MBTA therapy, with wild-type mice exhibiting a lower tumor incidence and smaller tumors compared with B cell-deficient mice. Increased IL-6 and TNF-alpha levels indicated severe inflammation and a potential cytokine storm in B cell-deficient mice. Neutralization of TNF-alpha ameliorated these complications but resulted in increased tumor recurrence. The results highlight the important role of B cells in enhancing the immune response and maintaining immune homeostasis during MBTA therapy. Our findings offer new insights into improving therapeutic outcomes.
- MeSH
- B-Lymphocytes * immunology MeSH
- Pheochromocytoma * immunology therapy MeSH
- Immunotherapy * methods MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Adrenal Gland Neoplasms * immunology therapy MeSH
- Tumor Necrosis Factor-alpha MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Intramural MeSH
BACKGROUND AND OBJECTIVE: While prostate cancer (PCa) incidence and mortality rates continue to rise, early detection of PCa remains highly controversial, and the research landscape is rapidly evolving. Existing systematic reviews (SRs) and meta-analyses (MAs) provide valuable insights, but often focus on single aspects of early detection, hindering a comprehensive understanding of the topic. We aim to fill this gap by providing a comprehensive SR of contemporary SRs covering different aspects of early detection of PCa in the European Union (EU) and the UK. METHODS: On June 1, 2023, we searched four databases (Medline ALL via Ovid, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) and Google Scholar. To avoid repetition of previous studies, only SRs (qualitative, quantitative, and/or MAs) were considered eligible. In the data, common themes were identified to present the evidence systematically. KEY FINDINGS AND LIMITATIONS: We identified 1358 citations, resulting in 26 SRs eligible for inclusion. Six themes were identified: (1) invitation: men at general risk should be invited at >50 yr of age, and testing should be discontinued at >70 yr or with <10 yr of life expectancy; (2) decision-making: most health authorities discourage population-based screening and instead recommend a shared decision-making (SDM) approach, but implementation of SDM in clinical practice varies widely; decision aids help men make more informed and value-consistent screening decisions and decrease men's intention to attempt screening, but these do not affect screening uptake; (3) acceptance: facilitators for men considering screening include social prompting by partners and clinician recommendations, while barriers include a lack of knowledge, low-risk perception, and masculinity attributes; (4) screening test and algorithm: prostate-specific antigen-based screening reduces PCa-specific mortality and metastatic disease in men aged 55-69 yr at randomisation if screened at least twice; (5) harms and benefits: these benefits come at the cost of unnecessary biopsies, overdiagnosis, and subsequent overtreatment; and (6) future of screening: risk-adapted screening including (prebiopsy) risk calculators, magnetic resonance imaging, and blood- and urine-based biomarkers could reduce these harms. To enable a comprehensive overview, we focused on SRs. These do not include the most recent prospective studies, which were therefore incorporated in the discussion. CONCLUSIONS AND CLINICAL IMPLICATIONS: By identifying consistent and conflicting evidence, this review highlights the evidence-based foundations that can be built upon, as well as areas requiring further research and improvement to reduce the burden of PCa in the EU and UK. PATIENT SUMMARY: This review of 26 reviews covers various aspects of prostate cancer screening such as invitation, decision-making, screening tests, harms, and benefits. This review provides insights into existing evidence, highlighting the areas of consensus and discrepancies, to guide future research and improve prostate cancer screening strategies in Europe.
- MeSH
- Early Detection of Cancer * MeSH
- European Union * MeSH
- Humans MeSH
- Prostatic Neoplasms * diagnosis MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Geographicals
- United Kingdom MeSH
Analyzovaný soubor obsahuje 28 případů tumorů tenkého střeva u psů. Průměrný věk pacientů byl 10,7 roku s rozmezím 4 až 14 let. Z hlediska pohlavní příslušnosti se tumory vyvinuly u 16 samců, 2 samců kastrátů, 6 fen a u 4 kastrovaných fen. Z uvedeného údaje je zřejmé, že výrazně častěji byli postiženi samci. Psi byli příslušníky 18 plemen. Pouze u plemen west highland white teriér (WHWT) a hlad- kosrstý retrívr (flat coated retriever, FCR) se tumory vyskytly ve dvou případech. Osm jedinců byli kříženci. S výjimkou hamartomu byly všechny tumory maligní. Adenokarcinom byl diagnostikován v 7 případech, mastocytom v 6 případech, gastrointestinální stromální tumor (GIST), leiomyosarkom a lymfom po třech případech. Myxosarkom se vyskytl u dvou jedinců a tumor z antigen-prezentujících makrofágů, neurofibrosarkom, mezoteliom a maligní fibrózní histiocytom byly diagnostikovány po jednom případě.
The analyzed file contains 28 cases of small intestinal tumors in dogs. The average age of the patients was 10.7 years with a range of 4 to 14 years. In terms of gender, tumors developed in 16 males, 2 castrated males, 6 females and 4 castrated females. It is clear from the above that males were significantly more often affected. The dogs belonged to 18 breeds. Only in the WHWT and FCR breeds did tumors occur in two cases. Eight individuals were crossbreeds. With the exception of hamartoma, all tumors were malignant. Adenocarcinoma was diagnosed in 7 cases, mastocytoma in 6 cases, GIST, leiomyosarcoma and lymphoma in three cases each. Myxosarcoma occurred in two individuals and antigen-presenting macrophage tumor, neurofibrosarcoma, mesothelioma and malignant fibrous histiocytoma were diagnosed in one case each.
BACKGROUND: Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions, identified through multiparametric magnetic resonance imaging (mpMRI), present a clinical challenge due to their equivocal nature in predicting clinically significant prostate cancer (csPCa). Aim of the study is to improve risk stratification of patients with PI-RADS 3 lesions and candidates for prostate biopsy. METHODS: A cohort of 4841 consecutive patients who underwent MRI and subsequent MRI-targeted and systematic biopsies between January 2016 and April 2023 were retrospectively identified from independent prospectively maintained database. Only patients who have PI-RADS 3 lesions were included in the final analysis. A multivariable logistic regression analysis was performed to identify covariables associated with csPCa defined as International Society of Urological Pathology (ISUP) grade group ≥2. Performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC), calibration, and net benefit. Significant predictors were then selected for further exploration using a Chi-squared Automatic Interaction Detection (CHAID) analysis. RESULTS: Overall, 790 patients had PI-RADS 3 lesions and 151 (19%) had csPCa. Significant associations were observed for age (OR: 1.1 [1.0-1.1]; p = 0.01) and PSA density (OR: 1643 [2717-41,997]; p < 0.01). The CHAID analysis identified PSAd as the sole significant factor influencing the decision tree. Cut-offs for PSAd were 0.13 ng/ml/cc (csPCa detection rate of 1% vs. 18%) for the two-nodes model and 0.09 ng/ml/cc and 0.16 ng/ml/cc for the three-nodes model (csPCa detection rate of 0.5% vs. 2% vs. 17%). CONCLUSIONS: For individuals with PI-RADS 3 lesions on prostate mpMRI and a PSAd below 0.13, especially below 0.09, prostate biopsy can be omitted, in order to avoid unnecessary biopsy and overdiagnosis of non-csPCa.
- MeSH
- Risk Assessment methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Multiparametric Magnetic Resonance Imaging * methods MeSH
- Prostatic Neoplasms * pathology diagnostic imaging diagnosis blood MeSH
- Prostate pathology diagnostic imaging MeSH
- Prostate-Specific Antigen * blood MeSH
- Retrospective Studies MeSH
- ROC Curve MeSH
- Aged MeSH
- Neoplasm Grading MeSH
- Image-Guided Biopsy methods MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
Radioligandová terapie, někdy označovaná i radiofarmaceutická terapie pomocí značeného prostatického specifického membránového antigenu (prostate specific membrane antigen, PSMA) u karcinomu prostaty, je používána zhruba deset let v západní Evropě u pacientů s pokročilým, kastračně rezistentním, metastazujícím onemocněním. V krátkém přehledovém článku jsou uvedeny současné indikace přípravku Pluvicto (177Lu značené PSMA), způsob a možnosti aplikace, nežádoucí účinky a očekávaný účinek léčby. Naznačen je i další směr vývoje radioligandové terapie do budoucna v léčbě časnějších stadií onemocnění karcinomu prostaty.
Summary Radioligand therapy (RLT) using labeled prostate specific membrane antigen (PSMA) in prostate cancer has been used for about ten years in Western Europe in patients with advanced, castration-resistant, metastatic disease. In this short review article, the current indications of Pluvicto (177Lu labeled PSMA), the method and possibilities of application, side effects and the expected effect of treatment are presented. Further direction of the development of RLT in the future in the treatment of earlier stages of prostate cancer disease is also indicated.
Compounds in sand fly saliva elicit specific immune responses that may play a role in the establishment of canine Leishmania infection. Although canine antibodies to anti-sand fly saliva antigens have been extensively studied, little is known about cellular immune responses against Phlebotomus perniciosus salivary proteins. This study aimed to explore humoral and T-cell-mediated immunity against P. perniciosus salivary proteins in dogs (n = 85) from Mallorca (Spain), a leishmaniosis-endemic area, and find correlations with demographic (age, sex, and breed) and parasite-specific immunological parameters. Anti-sand fly saliva IgG was examined using a P. perniciosus whole salivary gland homogenate (SGH) ELISA and recombinant salivary protein rSP03B ELISA. Interferon gamma (IFN-γ) release whole blood assays with L. infantum soluble antigen (LSA), SGH, and rSP03B were also performed. Positive correlations were found between IgG levels in the SGH and rSP03B tests and between concentrations of SGH IFN-γ and rSP03B IFN-γ. While concentrations of SGH IFN-γ and rSP03B IFN-γ were low and produced only by a minority of dogs (less than 20%), high levels and frequencies of LSA IFN-γ as well as anti-saliva IgG for SGH and rSP03B were detected in a majority of dogs (61% and 75%, respectively). LSA IFN-γ levels were positively correlated with age and Leishmania-specific antibodies. In conclusion, dogs from a leishmaniosis-endemic area presented high humoral immunity against P. perniciosus salivary proteins, but their cellular immunity to these proteins was low and less frequent.
- MeSH
- Immunity, Cellular * MeSH
- Endemic Diseases MeSH
- Insect Proteins * immunology MeSH
- Immunity, Humoral * MeSH
- Immunoglobulin G blood immunology MeSH
- Interferon-gamma MeSH
- Leishmaniasis * immunology veterinary epidemiology MeSH
- Dog Diseases * immunology parasitology epidemiology MeSH
- Phlebotomus * immunology MeSH
- Dogs MeSH
- Salivary Proteins and Peptides * immunology MeSH
- T-Lymphocytes * immunology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Dogs MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Spain MeSH
