The FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion-positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9-21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.
- Klíčová slova
- FGFR, Gene fusions, RNA sequencing, Sinonasal, Targeted therapy, Tyrosine kinase inhibitor,
- MeSH
- dlaždicobuněčné karcinomy hlavy a krku MeSH
- dospělí MeSH
- fenotyp MeSH
- fúzní onkogenní proteiny * genetika MeSH
- infekce papilomavirem * komplikace virologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery * genetika analýza MeSH
- nádory hlavy a krku * genetika patologie virologie MeSH
- proteiny asociované s mikrotubuly MeSH
- receptor fibroblastových růstových faktorů, typ 3 * genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- spinocelulární karcinom * genetika patologie virologie 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
- FGFR3 protein, human MeSH Prohlížeč
- fúzní onkogenní proteiny * MeSH
- nádorové biomarkery * MeSH
- proteiny asociované s mikrotubuly MeSH
- receptor fibroblastových růstových faktorů, typ 3 * MeSH
- TACC3 protein, human MeSH Prohlížeč
BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.
- Klíčová slova
- fibrotic focus, lymphovascular invasion, prognostic biomarkers, stromal tumor-infiltrating lymphocytes, triple-negative breast cancer,
- MeSH
- adjuvantní chemoterapie MeSH
- lidé MeSH
- nádorové biomarkery MeSH
- prognóza MeSH
- triple-negativní karcinom prsu * farmakoterapie patologie MeSH
- tumor infiltrující lymfocyty metabolismus patologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- nádorové biomarkery MeSH
We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.
- MeSH
- epilepsie * genetika MeSH
- klinické zkoušky jako téma MeSH
- kojenec MeSH
- lidé MeSH
- multiomika MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- prospektivní studie MeSH
- tuberózní skleróza * genetika MeSH
- vigabatrin terapeutické užití MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- vigabatrin MeSH
BACKGROUND: The SIOP-Renal Tumor Study Group (RTSG) does not advocate invasive procedures to determine histology before the start of therapy. This may induce misdiagnosis-based treatment initiation, but only for a relatively small percentage of approximately 10% of non-Wilms tumors (non-WTs). MRI could be useful for reducing misdiagnosis, but there is no global consensus on differentiating characteristics. PURPOSE: To identify MRI characteristics that may be used for discrimination of newly diagnosed pediatric renal tumors. STUDY TYPE: Consensus process using a Delphi method. POPULATION: Not applicable. FIELD STRENGTH/SEQUENCE: Abdominal MRI including T1- and T2-weighted imaging, contrast-enhanced MRI, and diffusion-weighted imaging at 1.5 or 3 T. ASSESSMENT: Twenty-three radiologists from the SIOP-RTSG radiology panel with ≥5 years of experience in MRI of pediatric renal tumors and/or who had assessed ≥50 MRI scans of pediatric renal tumors in the past 5 years identified potentially discriminatory characteristics in the first questionnaire. These characteristics were scored in the subsequent second round, consisting of 5-point Likert scales, ranking- and multiple choice questions. STATISTICAL TESTS: The cut-off value for consensus and agreement among the majority was ≥75% and ≥60%, respectively, with a median of ≥4 on the Likert scale. RESULTS: Consensus on specific characteristics mainly concerned the discrimination between WTs and non-WTs, and WTs and nephrogenic rest(s) (NR)/nephroblastomatosis. The presence of bilateral lesions (75.0%) and NR/nephroblastomatosis (65.0%) were MRI characteristics indicated as specific for the diagnosis of a WT, and 91.3% of the participants agreed that MRI is useful to distinguish NR/nephroblastomatosis from WT. Furthermore, all participants agreed that age influenced their prediction in the discrimination of pediatric renal tumors. DATA CONCLUSION: Although the discrimination of pediatric renal tumors based on MRI remains challenging, this study identified some specific characteristics for tumor subtypes, based on the shared opinion of experts. These results may guide future validation studies and innovative efforts. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 3.
- Klíčová slova
- Delphi technique, Wilms tumor, pediatric, renal tumor,
- MeSH
- delfská metoda MeSH
- difuzní magnetická rezonance MeSH
- lidé MeSH
- nádory ledvin * diagnostické zobrazování MeSH
- radiologie * MeSH
- Wilmsův nádor * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes - cell-adhesion molecule contactin-3. METHODS: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. RESULTS: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = - 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0-3 years old (fold change = - 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). CONCLUSIONS: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC.
- Klíčová slova
- Cell adhesion, Cerebral cortex development, Epilepsy, Neurodevelopmental disorders, mTORopathies,
- MeSH
- dítě MeSH
- dospělí MeSH
- down regulace MeSH
- kojenec MeSH
- kontaktiny * genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozek metabolismus MeSH
- novorozenec MeSH
- poruchy autistického spektra komplikace metabolismus MeSH
- předškolní dítě MeSH
- tuberózní skleróza * komplikace metabolismus MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- CNTN3 protein, human MeSH Prohlížeč
- kontaktiny * MeSH
Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
- Klíčová slova
- EP300, EWSR1, FOXO1, Gene fusion, Neuroepithelial tumor, PLAGL1, Supratentorial,
- MeSH
- dítě MeSH
- ependymom genetika MeSH
- lidé MeSH
- nádorové supresorové proteiny genetika MeSH
- onkogenní fúze MeSH
- proteiny buněčného cyklu genetika MeSH
- supratentoriální nádory genetika MeSH
- transkripční faktory genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- nádorové supresorové proteiny MeSH
- PLAGL1 protein, human MeSH Prohlížeč
- proteiny buněčného cyklu MeSH
- transkripční faktory MeSH
AIMS: Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most upregulated miRs in tubers. Here, we characterised miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR-34a. METHODS: We analysed the expression of miR-34a in resected cortical tubers (n = 37) compared with autopsy-derived control tissue (n = 27). The effect of miR-34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH-SY5Y cells following miR-34a transfection. RESULTS: The peak of miR-34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR-34a was also strongly expressed in foetal TSC cortex. Overexpression of miR-34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR-34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. CONCLUSIONS: MicroRNA-34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR-34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC.
- Klíčová slova
- TSC, mechanistic target of rapamycin, miRNA, migration, neurodevelopmental disorder,
- MeSH
- astrocyty metabolismus MeSH
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mozek růst a vývoj patologie MeSH
- mozková kůra patologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- neurony patologie MeSH
- předškolní dítě MeSH
- signální transdukce genetika MeSH
- tuberózní skleróza komplikace genetika patologie MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- mikro RNA MeSH
- MIRN34 microRNA, human MeSH Prohlížeč
- MIRN34a microRNA, mouse MeSH Prohlížeč
Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.
- Klíčová slova
- Colorectal cancer, FFPE clinical tissue samples, Idylla™ MSI assay, Microsatellite instability, Multi-center study,
- MeSH
- fixace tkání * MeSH
- fixativa MeSH
- formaldehyd MeSH
- imunohistochemie * MeSH
- kolorektální nádory chemie genetika patologie MeSH
- laboratorní automatizace MeSH
- lidé MeSH
- mikrosatelitní nestabilita * MeSH
- mutace * MeSH
- mutační analýza DNA * MeSH
- nádorové biomarkery * analýza genetika MeSH
- prediktivní hodnota testů MeSH
- reprodukovatelnost výsledků MeSH
- zalévání tkání do parafínu * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- srovnávací studie MeSH
- Názvy látek
- fixativa MeSH
- formaldehyd MeSH
- nádorové biomarkery * MeSH
PURPOSE: For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. METHODS: Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS ± RT) using Krippendorff's alpha (KA) and Gwet's AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. RESULTS: Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05-6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35-5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34-10.23) were independently associated with a higher iIBC risk. CONCLUSIONS: Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features.
- Klíčová slova
- Ductal carcinoma in situ, Interrater reliability, Invasive breast cancer, Risk stratification,
- MeSH
- duktální karcinom prsu * chirurgie MeSH
- intraduktální neinfiltrující karcinom * chirurgie MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- nádory prsu * chirurgie MeSH
- prognóza MeSH
- reprodukovatelnost výsledků MeSH
- segmentální mastektomie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
