Categorization systems for tick-borne encephalitis virus (TBEV) infection lack consistency in classifying disease severity. To evaluate the need for a standard, consensus-based categorisation system for TBEV infection across subtypes, we gathered an expert panel of clinicians and scientists with diverse expertise in TBEV infection. Consensus was sought using the Delphi technique, which consisted of 2 web-based survey questionnaires and a final, virtual, consensus-building exercise. Ten panellists representing 8 European countries participated in the Delphi exercise, with specialities in neurology, infectious disease, paediatrics, immunology, virology, and epidemiology. Panellists reached unanimous consensus on the need for a standardised, international categorisation system to capture both clinical presentation and severity of TBEV infection. Ideally, such a system should be feasible for use at bedside, be clear and easy to understand, and capture both the acute and follow-up phases of TBEV infection. Areas requiring further discussion were (1) the timepoints at which assessments should be made and (2) whether there should be a separate system for children. This Delphi panel study found that a critical gap persists in the absence of a feasible and practical classification system for TBEV infection. Specifically, the findings of our Delphi exercise highlight the need for the development of a user-friendly classification system that captures the acute and follow-up (i.e., outcome) phases of TBEV infection and optimally reflects both clinical presentation and severity. Development of a clinical categorisation system will enhance patient care and foster comparability among studies, thereby supporting treatment development, refining vaccine strategies, and fortifying public health surveillance.
- MeSH
- Delphi Technique * MeSH
- Encephalitis, Tick-Borne * epidemiology virology diagnosis MeSH
- Consensus MeSH
- Humans MeSH
- Encephalitis Viruses, Tick-Borne * classification MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Pathogenic alterations, namely, fusions and amplifications, of the GLI1 gene have been identified in various mesenchymal tumors, including pericytoma with t(7;12), plexiform fibromyxoma, gastroblastoma, and other malignant mesenchymal neoplasms arising in the soft tissues, as well as in various visceral organs. However, only three cases of GLI1-rearranged renal tumors have been reported to date, comprising two low-grade spindle cell tumors with GLI1::FOXO4 fusion along with one GLI1-rearranged case with an unknown fusion partner. In this study, we analyzed three cases with GLI1::FOXO4 fusion and overlapping morphology. One of the cases was reported previously, but an extended clinical and immunohistochemical information is provided. The studied cases occurred in 2 female and 1 male patients aged 35, 55, and 62 years (mean 51 years). All three tumors affected the renal parenchyma and grew as unencapsulated but well-circumscribed solid masses containing occasional entrapped and dilated renal tubules. The tumor cells were organized in cords, nests, or fascicles, had a round to spindled shape, and exhibited only mild nuclear atypia and minimal mitotic activity. They had a sparse eosinophilic to clear cytoplasm and were embedded in myxocollagenous stroma. Immunohistochemically, all cases expressed GLI1 (albeit with variable intensity) and harbored GLI1::FOXO4 fusion. All three patients were treated solely by complete surgical excision. Case 1 was alive with unknown disease status, case 2 was alive without evidence of disease, and case 3 died of unrelated causes. Our study doubles the number of reported cases with GLI1::FOXO4 fusion. The so far absolute predilection of this fusion for renal tumors, coupled with the absence of reports of other GLI1 fusions in tumors of the kidney, might indicate the potential existence of a distinct renal subtype with morphological features similar to other GLI1-altered tumors. All four reported cases had an uneventful follow-up which, together with their low-grade morphological features, suggests that these tumors might have a favorable prognosis.
- MeSH
- Adult MeSH
- Forkhead Transcription Factors * genetics MeSH
- Gene Rearrangement * MeSH
- Immunohistochemistry MeSH
- Middle Aged MeSH
- Humans MeSH
- Biomarkers, Tumor * genetics analysis MeSH
- Kidney Neoplasms * genetics pathology MeSH
- Zinc Finger Protein GLI1 * genetics MeSH
- Cell Cycle Proteins * genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
OBJECTIVE: Transgenic mice with fluorescent protein (FP) reporters take full advantage of new in vivo imaging technologies. Therefore, we generated a TRPC5- and a TRPA1-reporter mouse based on FP C-terminal fusion, providing us with better alternatives for studying the physiology, interaction and coeffectors of these two TRP channels at the cellular and tissue level. METHODS: We generated transgenic constructs of the murine TRPC5- and TRPA1-gene with a 3*GGGGS linker and C-terminal fusion to mCherry and mTagBFP, respectively. We microinjected zygotes to generate reporter mice. Reporter mice were examined for visible fluorescence in trigeminal ganglia with two-photon microscopy, immunohistochemistry and calcium imaging. RESULTS: Both TRPC5-mCherry and TRPA1-mTagBFP knock-in mouse models were successful at the DNA and RNA level. However, at the protein level, TRPC5 resulted in no mCherry fluorescence. In contrast, sensory neurons derived from the TRPA1-reporter mice exhibited visible mTag-BFP fluorescence, although TRPA1 had apparently lost its ion channel function. CONCLUSIONS: Creating transgenic mice with a TRP channel tagged at the C-terminus with a FP requires detailed investigation of the structural and functional consequences in a given cellular context and fine-tuning the design of specific constructs for a given TRP channel subtype. Different degrees of functional impairment of TRPA1 and TRPC5 constructs suggest a specific importance of the distal C-terminus for the regulation of these two channels in trigeminal neurons.
- MeSH
- Red Fluorescent Protein MeSH
- Trigeminal Ganglion metabolism MeSH
- Gene Knock-In Techniques * MeSH
- TRPC Cation Channels * genetics metabolism MeSH
- TRPA1 Cation Channel * genetics metabolism MeSH
- Luminescent Proteins * genetics metabolism MeSH
- Mice, Transgenic * MeSH
- Mice MeSH
- Recombinant Fusion Proteins metabolism genetics MeSH
- Calcium metabolism MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.
- MeSH
- Algorithms MeSH
- Exome genetics MeSH
- Genome, Human genetics MeSH
- Genomics methods MeSH
- Humans MeSH
- Survival of Motor Neuron 1 Protein genetics MeSH
- Survival of Motor Neuron 2 Protein genetics MeSH
- Sequence Analysis, DNA methods MeSH
- Exome Sequencing MeSH
- Muscular Atrophy, Spinal * genetics diagnosis MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3 -related neoplasms are rare in the head and neck and may pose diagnostic challenges. We herein describe 22 TFE3 fusion neoplasms affecting 11 males and 11 females aged 4 to 79 years (median, 25) and involving different head and neck sites: sinonasal cavities (n = 8), tongue (n = 4), oral cavity/oropharynx (n = 3), salivary glands (n = 2), orbit (n = 2), and soft tissue or unspecified sites (n = 3). Based on morphology and myomelanocytic immunophenotype, 10 tumors qualified as ASPS, 7 as PEComas (3 melanotic; all sinonasal), and 5 showed intermediate (indeterminate) histology overlapping with ASPS and PEComa. Immunohistochemistry for TFE3 was homogeneously strongly positive in all cases. Targeted RNA sequencing/FISH testing confirmed TFE3 fusions in 14 of 16 successfully tested cases (88%). ASPSCR1 was the most frequent fusion partner in ASPS (4 of 5 cases); one ASPS had a rare VCP::TFE3 fusion. The 6 successfully tested PEComas had known fusion partners as reported in renal cell carcinoma and PEComas ( NONO, PRCC, SFPQ , and PSPC1 ). The indeterminate tumors harbored ASPSCR1::TFE3 (n = 2) and U2AF2::TFE3 (n = 1) fusions, respectively. This large series devoted to TFE3-positive head and neck tumors illustrates the recently proposed morphologic overlap in the spectrum of TFE3 -associated mesenchymal neoplasms. While all PEComas were sinonasal, ASPS was never sinonasal and occurred in diverse head and neck sites with a predilection for the tongue. The indeterminate (PEComa-like) category is molecularly more akin to ASPS but shows different age, sex, and anatomic distribution compared with classic ASPS. We report VCP as a novel fusion partner in ASPS and PSPC1 as a novel TFE3 fusion partner in PEComa (detected in one PEComa). Future studies should shed light on the most appropriate terminological subtyping of these highly overlapping tumors.
- MeSH
- Sarcoma, Alveolar Soft Part * genetics pathology MeSH
- Child MeSH
- Adult MeSH
- Phenotype MeSH
- Genetic Predisposition to Disease MeSH
- Gene Rearrangement * MeSH
- In Situ Hybridization, Fluorescence MeSH
- Immunohistochemistry MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Biomarkers, Tumor * genetics analysis MeSH
- Head and Neck Neoplasms * genetics pathology chemistry MeSH
- Perivascular Epithelioid Cell Neoplasms * genetics pathology chemistry MeSH
- Child, Preschool MeSH
- Aged MeSH
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors * genetics MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
OBJECTIVES: The development of External Quality Assessment Schemes (EQAS) for clinical flow cytometry (FCM) is challenging in the context of rare (immunological) diseases. Here, we introduce a novel EQAS monitoring the primary immunodeficiency Orientation Tube (PIDOT), developed by EuroFlow, in both a 'wet' and 'dry' format. This EQAS provides feedback on the quality of individual laboratories (i.e., accuracy, reproducibility and result interpretation), while eliminating the need for sample distribution. METHODS: In the wet format, marker staining intensities (MedFIs) within landmark cell populations in PIDOT analysis performed on locally collected healthy control (HC) samples, were compared to EQAS targets. In the dry format, participants analyzed centrally distributed PIDOT flow cytometry data (n=10). RESULTS: We report the results of six EQAS rounds across 20 laboratories in 11 countries. The wet format (212 HC samples) demonstrated consistent technical performance among laboratories (median %rCV on MedFIs=34.5 %; average failure rate 17.3 %) and showed improvement upon repeated participation. The dry format demonstrated effective proficiency of participants in cell count enumeration (range %rCVs 3.1-7.1 % for the major lymphoid subsets), and in identifying lymphoid abnormalities (79.3 % alignment with reference). CONCLUSIONS: The PIDOT-EQAS allows laboratories, adhering to the standardized EuroFlow approach, to monitor interlaboratory variations without the need for sample distribution, and provides them educational support to recognize rare clinically relevant immunophenotypic patterns of primary immunodeficiencies (PID). This EQAS contributes to quality improvement of PID diagnostics and can serve as an example for future flow cytometry EQAS in the context of rare diseases.
BACKGROUND: Auer rods (AuRs) are prominent intracellular structures found almost exclusively in myeloid cell malignancies, such as acute myeloid leukemia (AML), chronic and juvenile myelomonocytic leukemia and myelodysplastic syndrome. Extremely rare AuRs have been reported in patients with acute lymphoblastic leukemia (ALL) or among ambiguous lineage leukemia patients with a dominantly lymphoblastic immunophenotype. PROCEDURE: We report diagnostic and follow-up data of an international cohort of 11 children suffering from leukemias with AuRs and with significant presence of T and myeloid markers, majority of whom categorized as early T-cell precursor (ETP, n = 7); or T-ALL (ETP status unknown, n = 2), ALAL (acute leukemia of ambiguous lineage, n = 1), and AML reclassified from ALAL (n = 1). We described other diagnostic details and treatment types and responses. Moreover, we summarize previously published data. RESULTS: Among the four patients who started and remained on ALL-type therapy, all were in the first complete remission, whereas both patients who started and remained on AML-type therapy relapsed and died. Of the patients who followed either a combined ALL/AML protocol (Interfant 06) or who switched from one of the two types of therapy to the other, one patient died, and the remaining four were in first complete remission at the most recent follow-up. We also searched for similar cases in the literature and found only three additional children with nonmyeloid leukemia and AuRs and 10 adults with this type of leukemia. CONCLUSIONS: Briefly, ALL- or combined ALL/AML-type therapy may be effective for treating AuR-positive leukemia patients with a lymphoid immunophenotype.
- MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology therapy immunology MeSH
- Leukemia, Myeloid, Acute pathology therapy immunology MeSH
- Child MeSH
- Immunophenotyping * MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Follow-Up Studies MeSH
- Child, Preschool MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Hormonálně pozitivní karcinom prsu s negativitou receptoru 2 pro lidský epidermální růstový faktor (human epidermal growth factor receptor 2, HER2) je nejčastějším subtypem tohoto onemocnění. Cílem léčby časného a lokálně pokročilého karcinomu prsu je dosažení trvalé remise onemocnění, a k tomu je standardně používána chemoterapie, adjuvantní hormonální terapie a nověji i cílená terapie v podobě inhibitorů cyklin dependentních kináz 4 a 6 (CDK4/6). Klinická studie NATALEE hodnotila účinnost a bezpečnost adjuvantního podání ribociklibu u pacientek s vysokým rizikem relapsu onemocnění, přičemž byly zařazovány pacientky jak s uzlinovým postižením, tak i vysoce rizikové pacientky bez uzlinového postižení. Studie prokázala benefit adjuvantní léčby ribociklibem u této skupiny pacientek a na základě dosažených výsledků je v současnosti ribociklib zařazen do léčebného algoritmu pacientek s hormonálně pozitivním HER2 negativním karcinomem prsu s vysokým rizikem relapsu onemocnění.
Hormone positive HER2 negative breast cancer is the most common subtype of this disease. The goal of treatment of early and locally advanced breast cancer is to achieve a durable remission of the disease and to achieve this goal chemotherapy, adjuvant hormonal therapy and more recently cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors targeted therapy are standardly used. The NATALEE clinical trial evaluated the efficacy and safety of ribociclib in adjuvant setting in patients at high risk of relapse, enrolling both patients with nodal involvement and high-risk patients without nodal involvement. The study demonstrated the benefit of adjuvant ribociclib in this group of patients and based on the results, ribociclib is currently included in the treatment algorithm for patients with hormone receptor positive HER2 negative breast cancer.
Karcinom endometria patří mezi nejčastější gynekologické malignity ve vyspělých zemích a jeho incidence dlouhodobě roste. S rozvojem molekulárního porozumění biologii nádoru se otevřela cesta k cílené a imunoterapeutické léčbě, zejména u podtypů s defektním mechanismem oprav chybného párování DNA (deficient mismatch repair, dMMR) nebo s mikrosatelitovou instabilitou (microsateUite instability-high, MSI-H). Článek uvádí přehled současných možností imunoterapie v léčbě pokročilého nebo recidivujícího karcinomu endometria, včetně kombinací s chemoterapií a cílenými léky, na základě aktuálních dat z klinických studií. Imunoterapie se stala novým standardem v léčbě určité části pacientek s karcinomem endometria. Klíčovou roli hraje molekulární stratifikace, bez níž nelze imunoterapii účinně a bezpečně nasadit.
Endometrial cancer is one of the most common gynecological malignancies in developed countries, and its incidence has been increasing for a long time. With the development of molecular understanding of tumor biology, the way to targeted and immunotherapeutic treatment has been opened, especially for subtypes with deficient mismatch repair (dMMR) or microsateUite instability-high (MSI-H). The article provides an overview of current immunotherapy options for the treatment of advanced or recurrent endometrial cancer, including combinations with chemotherapy and targeted drugs, based on current clinical trial data. Immunotherapy has become the new standard of care for some patients with endometrial cancer. Molecular stratification plays a key role, without which immunotherapy cannot be used effectively and safely.
Mezoblastický nefrom je nejčastější tumor ledvin u novorozenců a kojenců do 3 měsíců věku. Existují tři subtypy mezoblastického nefromu: klasický, celulární a smíšený. Jedná se o většinou benigní tumor, avšak celulární subtyp může vykazovat známky agresivního chování. Tato kazuistika popisuje případ pacienta s celulárním subtypem tumoru s patrnou heterogenní strukturou, cystickými okrsky a podle histologie s infiltrací okolní tukové tkáně a perineurální propagací. U pacienta byla při cytogenetickém vyšetření také prokázána fúze genů ETV6-NTRK3, která je typická pro celulární variantu a umožňuje její odlišení od varianty klasické. Léčba je chirurgická, volí se radikální nefrektomie, u vyšších stadií celulární varianty je doporučena také adjuvantní chemoterapie. Diferenciálně diagnosticky je problematické odlišení od maligního Wilmsova tumoru, existují charakteristiky spíše typické pro jednotlivé tumory, avšak spolehlivé odlišení bohužel není pomocí zobrazovacích metod vždy možné a diagnózu lze stanovit až pomocí histologického vyšetření.
Mesoblastic nephroma is the most common renal tumor in the neonatal period and infants less than three months old. There are three subtypes of mesoblastic nephroma: classic, cellular and mixed. It is mostly a benign tumor, although the cellular subtype may show signs of aggressive behavior. This case report describes a patient with a cellular subtype with heterogeneous structure, cystic degeneration and, according to histology, infiltration of the surrounding adipose tissue and perineural propagation. Cytogenetics also revealed the ETV6-NTRK3 gene fusion, which is typical for the cellular variant and allows its differentia- tion from the classic variant. The treatment of choice is surgical resection, adjuvant chemotherapy is advised for higher stages of cellular variant. Differential diagnosis from Wilms tumor is problematic, there are characteristics relatively typical for individual tumors, but absolute distinction is unfortunately not always possible by diagnostic imaging and the diagnosis can only be established by histological examination.
