ABSTRACT
AIMS: Most salivary gland neoplasms are distinguished by specific recurrent gene fusions. Recently, a subset of pleomorphic adenomas (PAs) originated from the parotid gland harboring the HMGA2::WIF1 fusion was described with a canalicular adenoma-like morphology and a greater propensity for recurrence and carcinomatous transformation. METHODS AND RESULTS: This study delineates the clinicopathological attributes of 54 cases of PAs exhibiting HMGA2 alterations, predominantly characterized by the HMGA2::WIF1 fusion, alongside a comparative analysis of their morphological and immunohistochemical profiles. The cohort consisted of 23 females and 31 males (n=54), mean age was 56.7 (25-84), tumors predominantly originated from the parotid gland (94.4%, 51/54), with 3 cases from seromucous glands (5.6%). Mean tumor size was 2.6 cm (0.8-7.5). No clinical difference (demographic, follow-up) was observed among histological subsets (conventional, hybrid, and pure). Complete excision was performed in all cases, with follow-up data available for 41% (22/54) of patients, showing 13.6% of recurrence (3/22) between 5 and 8 months. Various histological growth patterns were identified, with the pure hypercellular monomorphic subset being the most prevalent. The HMGA2::WIF1 gene was identified in all subsets without any particular predominance. Novel gene partners of HMGA2 were identified, comprising NRXN1, INPP4B, MSRB3, PHLDA1, and FLJ41278. CONCLUSIONS: The present study reports that the HMGA2::WIF1 gene fusion was present in all subsets of PAs without significant predominance. However, further investigations are warranted to explore the relationship between histological subsets of PAs and the molecular alterations underlying them.
ABSTRACT
Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we find that SF3B1-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.
Subject(s)
Myelodysplastic Syndromes , R-Loop Structures , Humans , Splicing Factor U2AF/genetics , Serine-Arginine Splicing Factors/genetics , RNA Splicing Factors/genetics , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Mutation , Transcription Factors/genetics , Phosphoproteins/geneticsABSTRACT
Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2, which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2Y641F rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.
Subject(s)
Enhancer of Zeste Homolog 2 Protein , Histones , Lymphoma, Follicular , Mutation , Polycomb Repressive Complex 2 , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Humans , Lymphoma, Follicular/genetics , Lymphoma, Follicular/metabolism , Polycomb Repressive Complex 2/genetics , Polycomb Repressive Complex 2/metabolism , Histones/metabolism , Histones/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Methylation , Chromatin/metabolism , Chromatin/genetics , Transcription, GeneticABSTRACT
BACKGROUND AND AIM: Ocular sarcoidosis is present in 30-60% of all sarcoidosis patients. Our purpose is to increase awareness of the various presentations of ocular sarcoidosis. METHODS: Short image-based clinical case report. RESULTS: We report on a case of ocular sarcoidosis presenting with unilateral choroidal nodules in a middle-aged man. Sarcoid uveitis is generally bilateral and rather symmetrical. However, choroidal nodules are an exception to this rule, as they generally arise unilaterally. Choroidal nodules are highly responsive to oral corticosteroids. When left untreated, they may evolve to chorioretinal atrophy and secondary choroidal neovascularization. CONCLUSIONS: Knowledge of this presentation of ocular sarcoidosis can help clinicians optimize treatment outcomes for patients.
ABSTRACT
PURPOSE: Intramuscular capillary-type hemangiomas (ICTHs) are rare entities, belonging to the group of intramuscular "hemangiomas." The diagnosis remains challenging. We aimed to assess the diagnostic criteria, treatments and outcomes of ICTHs. METHODS: This retrospective study collected all cases of ICTH followed up in 9 French hospital centers, reviewed by an adjudication expert group. RESULTS: Among 133 patients screened, 66 with ICTH were included. The median age of patients at diagnosis was 28.0 years, interquartile range (21.0---36.0). The lesion, mainly presenting as a gradually increasing mass (83.9%), was painless (88.9%) and was located in the head and neck (42.4%). MRI (available in all cases) mainly revealed a well-delineated lesion, isointense to the muscle on T1-weighted images, with enhancement after contrast injection; hyperintense on T2-weighted images; and containing flow voids. Among the 66 cases, 59 exhibited typical ICTH features and 7 shared some imaging features with arteriovenous malformations. These latter were larger than typical ICTHs and more painful and appeared on imaging as less well delimited and more heterogeneous tissue masses, with larger tortuous afferent arteries, earlier draining vein opacification and mild arteriovenous shunting. We propose to name these lesions arteriovenous malformation (AVM)-like ICTH. Pathological reports were similar in typical and AVM-like ICTH, showing capillary proliferation with mainly small-size vessels, negative for GLUT-1 and positive for ERG, AML, CD31 and CD34, with low Ki67 proliferation index (<10%), and adipose tissue. The most frequent treatment for ICTH was complete surgical resection (17/47, 36.2%), preceded in some cases by embolization, which led to complete remission. CONCLUSIONS: ICTH can be diagnosed on MRI when it is typical. Biopsy or angiography are required for atypical forms.
Subject(s)
Arteriovenous Malformations , Hemangioma , Humans , Adult , Retrospective Studies , Hemangioma/diagnostic imaging , Hemangioma/therapy , Magnetic Resonance Imaging , Neck/pathologyABSTRACT
AIMS: The discovery of tumour type-specific gene fusion oncogenes in benign and malignant salivary gland and sinonasal (SGSN) tumours has significantly increased our knowledge about their molecular pathology and classification. METHODS AND RESULTS: We developed a new targeted multiplexed next-generation sequencing (NGS)-based method that utilizes ligation dependent reverse-transcriptase polymerase chain reaction (LD-RT-PCR) to detect oncogenic fusion transcripts involving 116 genes, leading to 96 gene fusions known to be recurrently rearranged in these tumours. In all, 180 SGSN tumours (formalin-fixed, paraffin-embedded samples, 141 specimens and 39 core needle biopsies) from the REFCORpath (French network for rare head and neck cancers) with previously identified fusion genes by fluorescent in situ hybridisation (FISH), RT-PCR, or molecular immunohistochemistry were selected to test its specificity and sensitivity and validate its diagnostic use. Tested tumours encompassed 14 major tumours types, including secretory carcinoma, mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary gland intraductal carcinoma, clear cell carcinoma, pleomorphic adenoma, adamantinoma-like Ewing Sarcoma, EWSR1::COLCA2 sinonasal sarcoma, DEK::AFF2 sinonasal carcinoma, and biphenotypic sinonasal sarcoma. In-frame fusion transcripts were detected in 97.8% of cases (176/180). Gene fusion assay results correlated with conventional techniques (immunohistochemistry [IHC], FISH, and RT-PCR) in 176/180 tumours (97.8%). CONCLUSION: This targeted multiplexed NGS-based LD-RT-PCR method is a robust, highly sensitive method for the detection of recurrent gene fusions from routine clinical SGSN tumours. It can be easily customized to cover new fusions. These results are promising for implementing an integrated NGS system to rapidly detect genetic aberrations, facilitating accurate, genomics-based diagnoses, and accelerate time to precision therapies in SGSN tumours.
Subject(s)
Adenocarcinoma , Salivary Gland Neoplasms , Sarcoma, Ewing , Sarcoma , Humans , Reverse Transcriptase Polymerase Chain Reaction , Salivary Glands/pathology , Sarcoma, Ewing/diagnosis , Salivary Gland Neoplasms/diagnosis , Salivary Gland Neoplasms/genetics , Salivary Gland Neoplasms/pathology , High-Throughput Nucleotide Sequencing/methods , Oncogene Proteins, Fusion/genetics , Neoplasm Proteins/geneticsABSTRACT
(1) Background: In head and neck squamous cell carcinoma, tumor hypoxia has been associated with radio/chemoresistance and poor prognosis, whereas human papillomavirus (HPV)-positive status has a positive impact on treatment response and survival outcomes. The aim of this study was to evaluate the expression and the potential prognostic value of hypoxia-induced endogenous markers in patients treated for squamous cell carcinoma of the nasal cavity and paranasal sinuses (SNSCC), and their correlation with HPV status. (2) Methods: In this monocentric study, patients treated in a curative intent for a SNSCC were screened retrospectively. Protein expression of CA-IX, GLUT-1, VEGF, VEGF-R1, and HIF-1α was determined by immunohistochemical staining, scored, and then correlated with overall survival (OS) and locoregional recurrence free survival (LRRFS). HPV status was assessed and correlated with hypoxic markers. (3) Results: 40 patients were included. A strong expression of CA-IX, GLUT-1, VEGF, and VEGF-R1 was detected in 30%, 32.5%, 50%, and 37.5% of cases, respectively. HIF-1α was detected in 27.5% of cases. High CA-IX expression was associated in univariate analysis with poor OS (p = 0.035), but there was no significant association between GLUT-1, VEGF, VEGF-R1, and HIF-1α expression, and OS/LRRFS. There was no correlation found between HPV status and hypoxia-induced endogenous markers (all p > 0.05). (4) Conclusions: This study provides data on the expression of hypoxia-induced endogenous markers in patients treated for SNSCC and underlines the potential role of CA-IX as a prognostic biomarker for SNSCC.
ABSTRACT
Intramuscular capillary-type haemangiomas (ICTH) are rare vascular anomalies that can easily be misdiagnosed as other entities. A systematic review was performed of all cases of ICTH in the literature since its first description in 1972. An adjudication committee reviewed cases to include only ICTHs. Among 1,143 reports screened, 43 were included, involving 75 patients. The most frequent differential diagnosis was intramuscular venous malformations. The mean age of patients at diagnosis was 21.2 years. ICTH was mainly described as a gradually increasing mass (81.8%), painless (73.9%), that could occur anywhere in the body but most frequently on the head and neck (44.0%). Magnetic resonance imaging (MRI) was mainly used for diagnosis (69.1%) and displayed specific features. The most frequent treatment was complete surgical removal (73.9%), which could be preceded by embolization, and led to complete remission without recurrence in all but 1 case.
Subject(s)
Hemangioma, Capillary , Hemangioma , Vascular Malformations , Humans , Young Adult , Adult , Hemangioma/diagnostic imaging , Hemangioma/surgery , Vascular Malformations/diagnostic imaging , Vascular Malformations/therapy , Neck/blood supply , Neck/pathology , Hemangioma, Capillary/diagnostic imaging , Hemangioma, Capillary/surgery , Head/pathologyABSTRACT
The last 2 decades have attended a dynamic evolution in the nosology of poorly differentiated sinonasal tract malignancies, with several new molecularly defined entities having been described in addition to delineation of the genetic driver/s of some established older entities. These discoveries, however, mostly concerned epithelial-derived neoplasms (carcinomas). Adamantinoma-like Ewing sarcoma and biphenotypic sinonasal sarcoma are the major representatives of the newly defined mesenchymal categories. The colorectal cancer associated 2 (COLCA2) has been discovered recently as a colorectal cancer risk gene locus, but fusions involving this gene have not been well characterized. We, herein, describe clinicopathologic and molecular features of a novel sinonasal sarcoma characterized by undifferentiated spindle/round cell morphology and defined by recurrent EWSR1::COLCA2 fusions. All patients (n=5) were adults (3 female and 2 male) with a median age of 46 years (range, 23 to 60 y). The tumors originated in different subsites of the sinonasal tract with frequent multisite involvement. Original diagnoses were undifferentiated or unclassified round cell/spindle cell neoplasm/sarcoma (n=4) and neuroendocrine carcinoma (n=1). Surgery with or without adjuvant chemoradiation was the treatment in all cases. At the last follow-up, 1 patient developed multiple local recurrences over 21 years and another developed local recurrence and distant metastasis to bone 27 months after diagnosis. A third patient developed local recurrence 11 months later. Two patients were disease-free at 23, and 24 months. Histology showed nondescript highly cellular neoplasms with an admixture of spindled and round cells disposed into solid sheets and fascicles with brisk mitotic activity. Immunohistochemistry was negative for all lineage-specific markers with only limited focal membranous CD99 (4 of 5 cases) and weak pankeratin (1 of 5 cases) expression. Targeted RNA sequencing revealed an EWSR1::COLCA2 fusion, verified by EWSR1 fluorescence in situ hybridization, in all cases. This series identifies a novel member in the undifferentiated spindle/round cell sarcoma category with strong predilection for the sinonasal tract. None of >10,000 epithelial and mesenchymal neoplasms tested at the authors' centers during the same period showed this fusion, highlighting rarity of tumors carrying this gene fusion. Accordingly, molecular testing of unclassified sinonasal malignancies/sarcomas showing round and spindle cell morphology is recommended to enhance the identification and further characterization of this entity.
Subject(s)
Colorectal Neoplasms , Paranasal Sinus Neoplasms , Paranasal Sinuses , Sarcoma, Ewing , Sarcoma , Soft Tissue Neoplasms , Adult , Humans , Male , Female , Young Adult , Middle Aged , In Situ Hybridization, Fluorescence , Sarcoma/genetics , Sarcoma, Ewing/genetics , Paranasal Sinuses/pathology , Biomarkers, Tumor/genetics , Oncogene Proteins, Fusion/genetics , RNA-Binding Protein EWS/genetics , Neoplasm Proteins/geneticsABSTRACT
The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of "dural angioleiomyomas" (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.
Subject(s)
Angiomyoma , Connexins , Hemangioma , Angiomyoma/genetics , Connexins/genetics , DNA Methylation , Hemangioma/genetics , Humans , Mutation , Retrospective Studies , Gap Junction alpha-4 ProteinABSTRACT
X inactivation (XCI) is triggered by upregulation of XIST, which coats the chromosome in cis, promoting formation of a heterochromatic domain (Xi). XIST role beyond initiation of XCI is only beginning to be elucidated. Here, we demonstrate that XIST loss impairs differentiation of human mammary stem cells (MaSCs) and promotes emergence of highly tumorigenic and metastatic carcinomas. On the Xi, XIST deficiency triggers epigenetic changes and reactivation of genes overlapping Polycomb domains, including Mediator subunit MED14. MED14 overdosage results in increased Mediator levels and hyperactivation of the MaSC enhancer landscape and transcriptional program, making differentiation less favorable. We further demonstrate that loss of XIST and Xi transcriptional instability is common among human breast tumors of poor prognosis. We conclude that XIST is a gatekeeper of human mammary epithelium homeostasis, thus unveiling a paradigm in the control of somatic cell identity with potential consequences for our understanding of gender-specific malignancies.
Subject(s)
Mediator Complex/metabolism , Neoplastic Stem Cells/metabolism , RNA, Long Noncoding/metabolism , Breast Neoplasms/metabolism , Cell Differentiation , Epigenesis, Genetic , Humans , RNA, Long Noncoding/genetics , X Chromosome InactivationABSTRACT
The rabbit VX2 is a large animal model of cancer used for decades by interventional radiologists to demonstrate the efficacy of various locoregional treatments against liver tumors. What do we know about this tumor in the new era of targeted therapy and immune-oncology? The present paper describes the current knowledge on the clinics, biology, histopathology, and tumor microenvironment of VX2 based on a literature review of 741 publications in the liver and in other organs. It reveals the resemblance with human cancer (anatomy, vascularity, angiogenic profile, drug sensitivity, immune microenvironment), the differences (etiology, growth rate, histology), and the questions still poorly explored (serum and tissue biomarkers, genomic alterations, immune checkpoint inhibitors efficacy).
ABSTRACT
Epigenetic inheritance of gene expression states enables a single genome to maintain distinct cellular identities. How histone modifications contribute to this process remains unclear. Using global chromatin perturbations and local, time-controlled modulation of transcription, we establish the existence of epigenetic memory of transcriptional activation for genes that can be silenced by the Polycomb group. This property emerges during cell differentiation and allows genes to be stably switched after a transient transcriptional stimulus. This transcriptional memory state at Polycomb targets operates in cis; however, rather than relying solely on read-and-write propagation of histone modifications, the memory is also linked to the strength of activating inputs opposing Polycomb proteins, and therefore varies with the cellular context. Our data and computational simulations suggest a model whereby transcriptional memory arises from double-negative feedback between Polycomb-mediated silencing and active transcription. Transcriptional memory at Polycomb targets thus depends not only on histone modifications but also on the gene-regulatory network and underlying identity of a cell.
Subject(s)
Epigenesis, Genetic , Mammals/genetics , Polycomb-Group Proteins/genetics , Transcriptional Activation , Animals , Female , Histone Code , Humans , Male , Mice , Polycomb Repressive Complex 2/geneticsABSTRACT
In situforming tissue adhesives based on biopolymers offer advantages over conventional sutures and staples in terms of biocompatibility, biodegradability, ease of application and improved patient compliance and comfort. Here, we describe the evaluation ofin situgelling hydrogel system based on dextran dialdehyde (DDA) obtained by periodate oxidization of dextran and chitosan hydrochloride (CH) as tissue adhesive. The hydrogel was prepared by reacting aldehyde functions in DDA with the amino functions in CH via Schiff's reaction. The gelation reaction was instantaneous and took just 4 s. The DDA-CH hydrogel as tissue adhesive was evaluated on a sheep lung parenchymal injury model and a pig aortic model and was compared with the commercially available tissue sealant, Bioglue®. The DDA-CH glue could completely seal the sheep lung incision site even at inflation with air way pressure of 30 cm of H2O with no air leak observed in the incision sites (n= 8) in any of the animals. Histological analyses showed mild inflammation after 2 weeks, comparable to Bioglue®. Resorption of test material by giant cells with no adverse effect on lung parenchyma was seen after 3 months. The DDA-CH glue was also very effective in sealing aortic incisions in a pig model (n= 4) with no failures and aneurisms. The endoluminal surface of the sealed incision in all cases showed intact apposition with adequate healing across the incision. No tissue necrosis or inflammation of endothelial surface could be seen grossly. Our studies show that the DDA-CH hydrogel could function as an effective sealant for the prevention of air and blood leaks following lung and vascular surgery.
Subject(s)
Biocompatible Materials , Hydrogels , Lung Injury , Tissue Adhesives , Vascular System Injuries , Animals , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Chitosan/chemistry , Dextrans/chemistry , Hydrogels/chemistry , Hydrogels/pharmacology , Lung/drug effects , Lung/pathology , Lung Injury/metabolism , Lung Injury/pathology , Sheep , Sutureless Surgical Procedures/methods , Tissue Adhesives/chemistry , Tissue Adhesives/pharmacology , Vascular System Injuries/metabolism , Vascular System Injuries/pathologyABSTRACT
AIMS: Secretory carcinoma (SC) is characterized by ETV6 rearrangements, most often ETV6-NTRK3 fusion. Given its histologic overlap with other salivary gland tumors (SGTs), SCs can be difficult to diagnose without genetic confirmation. A recently developed pan-TRK (tropomyosin receptor kinase) antibody shows promise for identifying tumors with NTRK (neurotrophic tyrosine kinase receptor 3) fusions. The aim of this study was to evaluate the utility of pan-TRK immunohistochemistry in distinguishing SCs from mimics and selecting patients eligible for TRK inhibitor clinical trials. We examined whole-tissue sections from 111 SGTs with molecular characterization, including 26 SCs (23 with ETV6-NTRK3 fusion and 3 with ETV6-RET fusion detected by ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing and 85 non-SC SGTs (no ETV6-NTRK3 fusion). Immunohistochemistry was performed with a pan-TRK rabbit monoclonal antibody. When any pan-TRK staining (nuclear or cytoplasmic with any staining intensity) was considered to indicate positivity, 22 of 23 SCs with ETV6-NTRK3 fusion (95.7%) and 33 of 85 non-SC (38.8%) salivary neoplasms were positive, mainly basal cell adenoma, pleomorphic adenomas, adenoid cystic carcinomas, and epithelial-myoepithelial carcinomas. All SCs with ETV6-RET fusion were entirely negative. When only nuclear pan-TRK staining with any staining intensity was considered positive, 18 of 23 SCs with ETV6-NTRK3 fusion (78.3%) were positive, 11 among them with diffuse staining (>30% of cells). All non-SCs and SCs with ETV6-RET fusion were entirely negative. In comparison to molecular analysis (ligation-dependent reverse transcription-polymerase chain reaction, next-generation sequencing), nuclear pan-TRK IHC has a sensitivity of 78.3% and a specificity of 100% for diagnosing SCs with ETV6-NTRK3 fusion, 69% and 100% for SCs (all fusions). Pan-TRK is a reasonable screening test for diagnosing SCs among SGTs when taking only nuclear staining into account. Although pan-TRK expression is not entirely sensitive for SCs, nuclear staining is highly specific for SCs with ETV6-NTRK3 fusion. The lack of pan-TRK immunoreactivity in a subset of SCs is suggestive of atypical exons 4 to 14 or exons 5 to 14 ETV6-NTRK3 fusion or non-NTRK alternative fusion partners such as ETV6-RET. Pan-TRK staining can serve as a strong diagnostic marker to distinguish SC from it mimics and to select patients eligible for TRK inhibitor clinical trials.
Subject(s)
Biomarkers, Tumor/genetics , Gene Fusion , Gene Rearrangement , Immunohistochemistry , Oncogene Proteins, Fusion/genetics , Receptor, trkC/genetics , Salivary Gland Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Female , France , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Multiplex Polymerase Chain Reaction , Phenotype , Predictive Value of Tests , Reproducibility of Results , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Salivary Gland Neoplasms/pathology , Young AdultABSTRACT
Genes involved in 3'-splice site recognition during mRNA splicing constitute an emerging class of oncogenes. SF3B1 is the most frequently mutated splicing factor in cancer, and SF3B1 mutants corrupt branchpoint recognition leading to usage of cryptic 3'-splice sites and subsequent aberrant junctions. For a comprehensive determination of alterations leading to this splicing pattern, we performed a pan-TCGA screening for SF3B1-specific aberrant acceptor usage. While the most of aberrant 3'-splice patterns were explained by SF3B1 mutations, we also detected nine SF3B1 wild-type tumors (including five lung adenocarcinomas). Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factor SUGP1 in five of these cases. Modeling of SUGP1 loss and mutations in cell lines showed that both alterations induced mutant-SF3B1-like aberrant splicing. Our study provides definitive evidence that genetic alterations of SUGP1 genocopy SF3B1 mutations in lung adenocarcinoma and other cancers.
Subject(s)
Adenocarcinoma of Lung/genetics , Lung Neoplasms/genetics , Mutation , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Cell Line, Tumor , Codon Usage , Computer Simulation , HEK293 Cells , Humans , Loss of Heterozygosity , RNA Splice Sites , Sequence Analysis, RNAABSTRACT
OBJECTIVE: Preoperative embolization of juvenile nasopharyngeal angiofibroma (JNA) is usually performed by the occlusion of branches of the external carotid artery (ECA). However, a significant proportion of JNAs also receive blood from the internal carotid artery (ICA). The objective of this study was to report on the feasibility and clinical impact of superselective embolization of ICA branches in complex cases of JNA. METHODS: This was a single-center retrospective study of all patients operated on for JNA between 2000 and 2018. The patients treated with embolization of branches of the ICA were identified. The results in terms of complications, intraoperative blood loss, and rate of residual disease were analyzed and compared to those of a control group of patients treated only with embolization of ECA branches and matched by age, stage, angiographic pattern, surgical approach, and previous surgery. RESULTS: Ninety-two patients were included. Embolization of branches of the ICA was attempted in 14 cases of advanced or recurrent tumors and was ultimately possible in nine cases. There were no complications after embolization. The mean intraoperative blood loss was 1428 mL. Residual disease was found in three cases (33%). There was no significant difference compared with the control group (mean intraoperative blood loss = 1355 mL, residual disease = 4 (44%); all P > .05). CONCLUSION: In this retrospective study, we report the feasibility of superselective embolization of ICA branches in selected cases of JNA. There was no observed benefit of this technique in terms of intraoperative bleeding or decreased risk of residual disease. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E775-E780, 2021.
Subject(s)
Angiofibroma/therapy , Carotid Artery, Internal/surgery , Embolization, Therapeutic/methods , Nasopharyngeal Neoplasms/therapy , Preoperative Care/methods , Adolescent , Adult , Angiography , Blood Loss, Surgical , Carotid Artery, External/surgery , Child , Feasibility Studies , Female , Humans , Male , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
The study of vascular anomalies, "angiomas", vascular tumours and vascular malformations is made difficult by the great variety and confusion of the names used in the literature for these diseases, some of which are rare. The great merit of the classification proposed by the International Society for the Study of Vascular Anomalies (ISSVA), adopted in 2014 and modified in 2018, is to propose a unambiguous nomenclature and to try to group these lesions in a logical way, contrasting with the lists of the usual "classifications". This classification is based on the distinction between proliferative lesions (tumours and reactive lesions) and those which are due to a congenital anomaly of vascular morphogenesis (vascular malformations). It incorporates recent data on the molecular causes of these diseases. The major groups of lesions recognised in this classification will be presented and some lesions of interest briefly discussed. This classification aims to be usable by all medical specialties and applicable to all tissues and organs, even if efforts are still needed to integrate organ-specific names in order to unify the nomenclature and eliminate confusion. Even if it does not solve all the problems in this complex field, the unification of the nomenclature is a major contribution of this classification and pathologists are strongly encouraged to refer to it in daily practice.
Subject(s)
Hemangioma , Vascular Malformations , Vascular Neoplasms , Humans , Vascular Malformations/diagnosisABSTRACT
Intrahepatic lesions in adults, commonly named hepatic hemangioma, should be called Intrahepatic Venous Malformations (IHVM), or Giant Intrahepatic Venous Malformations (GIHVM) when larger than 10 cm according to the ISSVA classification (International society study group for vascular anomalies). Localized coagulation disorders (LIC) in patients with venous malformations are quite commonly associated in venous malformations, they result in decreased fibrinogen (< 2g/l) and elevated d-dimers (> 1500 ng/ml) and might be responsible of intralesional thrombotic, pain or bleeding episodes.We report a case report of a 41 y/o patient that presented with right hypochondrium pain episodes discovering an unknown GIHVM on ultrasound imaging with a prior history of uterine bleeding episodes and multiples miscarriages.On laboratory work up the patient presented an associated localized Intravascular Coagulation (LIC) with the GIHVM. As the patient desire to become pregnant was important our multidisciplinary clinic allowed a pregnancy with close clinical, biological and imaging monitoring and follow up. Early initiation of low molecular weighted heparin (LMWH) successfully allowed an uncomplicated term pregnancy and delivery. Intrahepatic lesion stability was achieved and prevented progression from LIC to diffuse intravascular coagulation disorder (DIC)..
Subject(s)
Blood Coagulation Disorders/etiology , Hemangioma/complications , Liver Neoplasms/complications , Abortion, Habitual/etiology , Adult , Anticoagulants/administration & dosage , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/drug therapy , Cesarean Section , Enoxaparin/administration & dosage , Female , Hemangioma/diagnostic imaging , Hemangioma/therapy , Humans , Live Birth , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/therapy , Pregnancy , Treatment Outcome , Tumor BurdenABSTRACT
OBJECTIVES: To report the outcomes of surgical treatment of calf intramuscular venous malformations (IMVMs) on pain, functional limitation, and quality of life. METHODS: We retrospectively reviewed 57 consecutive patients who had surgery for IMVM of the posterior compartment of the leg between 2010 and 2015. Treatments were all done at a single institution. RESULTS: Patients presented with pain (52), muscle contracture (14), or pulmonary embolism (4). Muscle involvement included the soleus muscle (n = 28, 49%), the gastrocnemius muscle (n = 25, 43%), and deep muscles (n = 4, 7%). Complete excision was possible in 52 patients (91%) and partial excision in 5 (9%). Thirty-five of 46 patients who had an MRI follow-up at six months had no residual venous malformation. At the final follow-up (mean 39 months), 32 of 40 patients seen had no residual pain and 37 had no residual functional impairment. CONCLUSION: In cases where IMVM is located in one muscle in the leg, we demonstrated that surgery yielded improvement in pain, function, and quality of life.