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Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome-sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, H3F3A (47.1%), TP53 (29.4%), NF1 (19.6%), ATRX (17.6%), and PPM1D (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: HNRNPC, SYNE1, and RBM10. Several germline mutations, including three variants (SLC16A8 rs2235573, LMF1 rs3751667, FAM20C rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene CDK4 was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.
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Astrocitoma , Glioma , Humanos , Fosfatidilinositol 3-Quinasas , Mutación , Glioma/genética , Médula Espinal/patología , Proteínas de Unión al ARN/genéticaRESUMEN
Endoplasmic reticulum (ER) stress and subsequent apoptosis played vital role in liver injury and dysfunction. The aim of this study was to investigate the protective effect and mechanism of salidroside on hypoxia induced liver injury both in vivo and in vitro. Male SD rats were exposed to hypobaric chamber to simulate high altitude hypoxia model. High altitude hypoxia led to significant liver injury and apoptosis, increased the expression levels of p-JNK, BAX and ER stress markers. Salidroside treatment significantly inhibited hypoxia induced ER stress by decreasing the protein expression of glucose-regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated inositol-requiring enzyme 1α (p-IRE1α). In addition, salidroside treatment also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins p-JNK, TRAF2, BAX, and cleaved caspase 9 and caspase 12, as well as upregulation of Bcl-2. Furthermore, in vitro study found that blocking IRE1α pathway using specific inhibitor STF-083010 subsequently reversed the protective effect of salidroside on liver apoptosis. Taken together, our findings revealed that salidroside exerts protective effects against hypoxia induced liver injury through inhibiting ER stress mediated apoptosis via IRE1α/JNK pathway.
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Estrés del Retículo Endoplásmico/efectos de los fármacos , Glucósidos/uso terapéutico , Hipoxia/tratamiento farmacológico , Hepatopatías/tratamiento farmacológico , Fenoles/uso terapéutico , Sustancias Protectoras/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Línea Celular , Chaperón BiP del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Humanos , Hipoxia/complicaciones , Hipoxia/metabolismo , Hepatopatías/etiología , Hepatopatías/metabolismo , MAP Quinasa Quinasa 4/metabolismo , Masculino , Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Oncogenic fusions are rare in colorectal carcinomas, but may be important for prognosis and therapy. An effective strategy for screening targetable oncogenic fusions in colorectal carcinomas is needed. Here, we investigate molecular genetic alterations in colorectal carcinomas based on their DNA mismatch repair status, and to effectively screen for targetable oncogenic fusions in colorectal carcinomas. In this retrospective study, the initial cohort included 125 consecutive mismatch repair-deficient and 238 randomly selected mismatch repair-proficient colorectal carcinomas diagnosed between July 2015 and December 2017 at Peking Union Medical College Hospital. Targeted sequencing was performed. MLH1 promoter hypermethylation analysis was further employed for subgrouping dMMR colorectal carcinomas. Clinicopathological characteristics, molecular features, and survival outcome of colorectal carcinomas harboring oncogenic fusions were assessed. A multicenter cohort comprised of 227 colorectal carcinomas with dual loss of MLH1/PMS2 was used to validate the efficacy of the proposed screening strategy for oncogenic fusions. Of the 363 patients in the initial cohort, 11(3.0%) harbored oncogenic fusions and were all mismatch repair-deficient colorectal carcinomas with hypermethylated MLH1 and wild-type BRAF and KRAS, comprising 55% (11/20) of this subgroup. These patients with oncogenic fusions showed poorer 3-year cancer-specific survival compared with other Stage III/IV mismatch repair-deficient colorectal carcinoma patients (40% vs. 97%), and significantly higher CD274(PD-L1) expression in tumor cells compared with other dMMR colorectal carcinoma patients (46% vs. 6.1%, P < 0.001). An easy-to-perform and cost-efficient strategy for screening targetable fusions was proposed based on the current molecular testing algorithms for colorectal carcinomas, and validated in an independent multicenter cohort. In conclusion, oncogenic fusions were highly enriched and frequently detected in mismatch repair-deficient colorectal carcinomas with MLH1 hypermethylation and wild-type BRAF and KRAS, and were associated with poor prognosis and high tumor CD274(PD-L1) expression.
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Neoplasias Encefálicas/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Homólogo 1 de la Proteína MutL/genética , Síndromes Neoplásicos Hereditarios/genética , Fusión de Oncogenes/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Antígeno B7-H1/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Reparación de la Incompatibilidad de ADN , Reordenamiento Génico , Humanos , Mutación , Síndromes Neoplásicos Hereditarios/mortalidad , Síndromes Neoplásicos Hereditarios/patología , Pronóstico , Regiones Promotoras Genéticas , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Follicular dendritic cell sarcoma is a very rare bladder tumor with very few cases that have been reported in the English literature. CASE PRESENTATION: We report an unusual case of follicular dendritic cell sarcoma that is coexistent with urothelial carcinoma (UC) in the urinary bladder of a 73-year-old man, who first presented with lower abdominal pain. Microscopic examination of the first transurethral resection of bladder tumor (TURBT) sample showed a neoplasm containing spindle or ovoid-shaped cells that were arranged in storiform, nested or swirling patterns. Abundant mitotic Figs. (30 mitoses/10 high-power fields) and apoptotic bodies were present. The tumor cells were positive for CD21 and vimentin, partly positive for CD23, D2-40 and CD35. After 6 weeks, the tumor recurred lately, which surprisingly contained a component of urothelial carcinoma. The first TURBT sample was then reviewed and a coexisting UC mixed with FDCS was identified by examining the deeper levels of the tumor blocks. CONCLUSIONS: This case is, to our knowledge, the first time to report the coexistence of FDCS and UC in the urinary bladder of an elderly patient. And these two tumors may share a similar molecular mechanism.
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Carcinoma de Células Transicionales/patología , Sarcoma de Células Dendríticas Foliculares/patología , Neoplasias Primarias Múltiples/patología , Neoplasias de la Vejiga Urinaria/patología , Anciano , Humanos , MasculinoRESUMEN
OBJECTIVE: To study the expression and prognostic significance of ERG and SPINK1 expression in endocrine-treated prostatic cancer. METHODS: Prostatic needle biopsies from 118 prostatic cancer patients primarily treated with endocrine therapy were reviewed. Immunohistochemical study for ERG and SPINK1 protein was carried out. RESULTS: Co-expression of ERG and SPINK1 was not observed. The frequency of ERG protein expression in the 118 biopsies studied was 9.3% (11/118). The positive expression correlated with T stage (P=0.04) but not with patient age at diagnosis, prostatic specific antigen level, Gleason's score, M stage, tumor area and progression-free survival. Positive expression of SPINK1 was demonstrated in 11.0% (13/118) of the biopsies. SPINK1-positive cases carried a significantly shorter progression-free survival, as compared with SPINK1-negative cases (P=0.022). The expression was not associated with any other clinicopathologic variables. The following expression pattern showed statistically significant correlation with the clinical progress (P=0.029): ERG+/SPINK1- (11/118, 9.3%), ERG-/SPINK1+ (13/118, 11.0%) and ERG-/SPINK1- (94/118, 79.7%). CONCLUSIONS: ERG and SPINK1 proteins are mutually exclusive.SPINK1 expression is associated with more aggressive clinical behavior and can serve as a prognostic biomarker in prostatic cancer.
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Proteínas Portadoras/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Transactivadores/metabolismo , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata/tratamiento farmacológico , Regulador Transcripcional ERG , Inhibidor de Tripsina Pancreática de KazalRESUMEN
High-altitude hypoxia may disturb the metabolic modulation and function of both adipose tissue and liver. The endoplasmic reticulum (ER) is a crucial organelle in lipid metabolism and ER stress is closely correlated with lipid metabolism dysfunction. The aim of this study is to elucidate whether the inhibition of ER stress could alleviate hypoxia-induced white adipose tissue (WAT) lipolysis and liver lipid accumulation-mediated hepatic injury. A rat model of high-altitude hypoxia (5500 m) was established using hypobaric chamber. The response of ER stress and lipolysis-related pathways were analyzed in WAT under hypoxia exposure with or without 4-phenylbutyric acid (PBA) treatment. Liver lipid accumulation, liver injury, and apoptosis were evaluated. Hypoxia evoked significant ER stress in WAT, evidenced by increased GRP78, CHOP, and phosphorylation of IRE1α, PERK. Moreover, Lipolysis in perirenal WAT significantly increased under hypoxia, accompanied with increased phosphorylation of hormone-sensitive lipase (HSL) and perilipin. Treatment with 4-PBA, inhibitor of ER stress, effectively attenuated hypoxia-induced lipolysis via cAMP-PKA-HSL/perilipin pathway. In addition, 4-PBA treatment significantly inhibited the increase in fatty acid transporters (CD36, FABP1, FABP4) and ameliorated liver FFA accumulation. 4-PBA treatment significantly attenuated liver injury and apoptosis, which is likely resulting from decreased liver lipid accumulation. Our results highlight the importance of ER stress in hypoxia-induced WAT lipolysis and liver lipid accumulation.
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Current diagnosis of glioma types requires combining both histological features and molecular characteristics, which is an expensive and time-consuming procedure. Determining the tumor types directly from whole-slide images (WSIs) is of great value for glioma diagnosis. This study presents an integrated diagnosis model for automatic classification of diffuse gliomas from annotation-free standard WSIs. Our model is developed on a training cohort (n = 1362) and a validation cohort (n = 340), and tested on an internal testing cohort (n = 289) and two external cohorts (n = 305 and 328, respectively). The model can learn imaging features containing both pathological morphology and underlying biological clues to achieve the integrated diagnosis. Our model achieves high performance with area under receiver operator curve all above 0.90 in classifying major tumor types, in identifying tumor grades within type, and especially in distinguishing tumor genotypes with shared histological features. This integrated diagnosis model has the potential to be used in clinical scenarios for automated and unbiased classification of adult-type diffuse gliomas.
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Neoplasias Encefálicas , Aprendizaje Profundo , Glioma , Adulto , Humanos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neuropatología , Glioma/diagnóstico por imagen , Glioma/genéticaRESUMEN
Background and Objectives: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebrovascular disease caused by homozygous or compound heterozygous variations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. However, several studies in recent years have found that some heterozygous HTRA1 mutations also cause cerebral small vessel disease (CSVD). The current study aims to report the novel genotypes, phenotypes, and histopathologic results of 3 pedigrees of CSVD with heterozygous HTRA1 mutation. Methods: Three pedigrees of familiar CSVD, including 11 symptomatic patients and 3 asymptomatic carriers, were enrolled. Whole-exome sequencing was conducted in the probands for identifying rare variants, which were then evaluated for pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Sanger sequencing was performed for validation of mutations in the probands and other family members. The protease activity was assayed for the novel mutations. All the participants received detailed clinical and imaging examinations and the corresponding results were concluded. Hematoma evacuation was performed for an intracerebral hemorrhage patient with the p.Q318H mutation, and the postoperative pathology including hematoma and cerebral small vessels were examined. Results: Three novel heterozygous HTRA1 mutations (p.Q318H, p.V279M, and p.R274W) were detected in the 3 pedigrees. The protease activity was largely lost for all the mutations, confirming that they were loss-of-function mutations. The patients in each pedigree presented with typical clinical and imaging features of CVSD, and some of them displayed several new phenotypes including color blindness, hydrocephalus, and multiple arachnoid cysts. In addition, family 1 is the largest pedigree with heterozygous HTRA1 mutation so far and includes homozygous twins, displaying some variation in clinical phenotypes. More importantly, pathologic study of a patient with p.Q318H mutation showed hyalinization, luminal stenosis, loss of smooth muscle cells, splitting of the internal elastic lamina, and intramural hemorrhage/dissection-like structures. Discussion: These findings broaden the mutational and clinical spectrum of heterozygous HTRA1-related CSVD. Pathologic features were similar with the previous heterozygous and homozygous cases. Moreover, clinical heterogeneity was revealed within the largest single family, and the mechanisms of the phenotypic heterogenetic remain unclear. Overall, heterozygous HTRA1-related CSVD should not be simply taken as a mild type of CARASIL as previously considered.
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BACKGROUND: Neuroendocrine carcinomas of the gastrointestinal tract (GI-NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs. METHODS: Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed, paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. RESULTS: In total, 143 GI-NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty-three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low-density lipoprotein receptor-related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT-ß-catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI-NECs harbored putative clinically relevant alterations, and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI-NECs first gain clonal mutations in TP53, RB1, NOTCH1 and APC, followed by subsequent whole-genome doubling (WGD) and post-WGD clonal mutations in LRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb-b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations. CONCLUSIONS: GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI-NECs.
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Carcinoma Neuroendocrino , Variaciones en el Número de Copia de ADN , Humanos , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Mutación , Tracto Gastrointestinal/patología , GenómicaRESUMEN
The characteristics of H3.3 G34-mutant gliomas in adults have yet to be specifically described. Thirty adults with H3.3 G34-mutant diffuse gliomas were retrospectively reviewed for clinical and pathologic information. Molecular profiling using next-generation sequencing was performed in 29 of the 30 H3.3 G34-mutant patients with 1 patient lacking available tumor samples, as well as 82 IDH/H3 wild-type adult diffuse glioma patients. The age at diagnosis of H3.3 G34-mutant diffuse gliomas was significantly younger than IDH/H3 wild-type gliomas (24 vs. 57 y, P<0.001). Overall, 19 of the 30 patients were diagnosed of glioblastoma with the primitive neuronal component, and 8 were glioblastoma. The molecular profiling analysis revealed higher frequencies of Olig-2 loss of expression, TP53 mutation, ATRX mutation, PDGFRA mutation, and MGMT promoter methylation (P<0.05) in H3.3 G34-mutant gliomas than IDH/H3 wild-type gliomas. No TERT promoter mutation and only 1 case of EGFR amplification were detected in the H3.3 G34-mutant cohort, the frequencies of which were significantly higher in the IDH/H3 wild-type cohort. A dismal prognosis was observed in H3.3 G34-mutant patients comparing to IDH/H3 wild-type cohort (overall survival: 14 vs. 22 mo; P=0.026). Univariate and multivariate analyses showed that the extent of resection and TP53 mutation were independently affecting prognosis. The distinct pathologic and molecular features of H3.3 G34-mutant diffuse gliomas in adult patients demonstrated the clinical importance of detecting H3.3 G34R/V mutations. The dismal prognosis of this rare high-grade glioma disease we reported here would further promote the investigation of dedicated therapeutic strategies.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Mutación , Adolescente , Adulto , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Femenino , Predisposición Genética a la Enfermedad , Glioma/mortalidad , Glioma/patología , Glioma/cirugía , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Fenotipo , Supervivencia sin Progresión , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
High-altitude hypoxia-induced oxidative stress and inflammation played an essential role in the incidence and development of liver injury. Salidroside (Sal), a phenylpropanoid glycoside extracted from the plant Rhodiola rosea, has recently demonstrated antioxidant, anti-inflammatory, and antihypoxia properties. Herein, we hypothesized that salidroside may alleviate hypoxia-induced liver injury via antioxidant and antiinflammatory-related pathways. A high-altitude hypoxia animal model was established using hypobaric chamber. Male SD rats were randomly divided into the control group, hypoxia group, control +Sal group, and hypoxia +Sal group. Salidroside treatment significantly inhibited hypoxia-induced increases of serum and hepatic pro-inflammatory cytokines release, hepatic ROS production and MDA contents; attenuated hypoxia-induced decrease of hepatic SOD, CAT, and GSH-Px activities. Furthermore, salidroside treatment also potentiated the activation of Nrf2-mediated anti-oxidant pathway, as indicated by upregulation of n-Nrf2 and its downstream HO-1 and NQO-1. In vitro study found that blocking the Nrf2 pathway using specific inhibitor ML385 significantly reversed the protective effect of salidroside on hypoxia-induced liver oxidative stress. In addition, salidroside treatment significantly inhibited hepatic pro-inflammatory cytokines release via JAK2/STAT3-mediated pathway. Taken together, our findings suggested that salidroside protected against hypoxia-induced hepatic oxidative stress and inflammation via Nrf2 and JAK2/STAT3 signaling pathways.
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BACKGROUND: Nonsense mutation or inactivation of SMARCA4 (BRG1) is associated with a monomorphic undifferentiated histological appearance in tumors at different sites. The association between SMARCA4 alteration and undifferentiated colonic carcinoma needs to be further elucidated. METHODS: A 61-year-old male patient presented to the hospital with intermittent epigastric pain in the right upper abdomen and abdominal distension. The enhanced computed tomography detected a mass in the hepatic flexure of the colon and multiple liver metastases. RESULTS: The right hemicolectomy contained a 4.5-cm undifferentiated malignancy with cells arranged in sheets, abundant necrosis, and areas showing rhabdoid morphology. The immunohistochemistry result showed that these tumor cells were focally positive for cytokeratin (CK), CK8, and CK18; however, diffusely positive for vimentin, P53, Fli-1, and SALL-4. Notably, tumor cells showed a heterogeneous loss of SMARCA4 expression pattern and intact SMARCB1 expression. Next-generation sequencing showed a germline SMARCA4 c.3277C>T(p.R1093*)mutation, somatic APC mutation, and no abnormal SMARCB1 gene. The tumor exhibited microsatellite stability, negative PD-L1 expression, and few infiltrating CD8 + T cells. The patient died a month later after surgery. CONCLUSIONS: We presented a rare case of undifferentiated colonic neoplasm with loss of SMARCA4 protein expression and germline SMARCA4 mutation. Moreover, the role of SMARCA4 alterations in tumor diagnosis and treatment was also summarized.
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Biomarcadores de Tumor/deficiencia , Biomarcadores de Tumor/genética , Neoplasias del Colon/química , Neoplasias del Colon/genética , ADN Helicasas/deficiencia , ADN Helicasas/genética , Mutación de Línea Germinal , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Resultado Fatal , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Fenotipo , Resultado del TratamientoRESUMEN
Primary tumors of the spinal cord are rare, accounting for 3-6% of tumors in the central nervous system, particularly in children. KIAA1549-BRAF fusion is more common in pilocytic astrocytoma (PA) and IDH1 R132H mutation is rare in infratentorial tumors. Here, we report a 10-year-old male patient who presented with weakness in lower limbs that progressed to difficulty walking. Magnetic resonance imaging (MRI) revealed an intramedullary solid-cystic lesion from the medulla oblongata to the thoracic spin 4 level, with the expansion of the spinal cord. The lesion exhibited patchy enhancement at C4-T1, indicating a tentative diagnosis of astrocytoma. The patient underwent resection of the lesion in the spinal canal from the cervical 6 level to the thoracic 2 level. Histopathology confirmed diagnosis of astrocytoma, WHO grade 2. Genetic analysis showed both IDH1 R132H mutation and KIAA1549-BRAF fusion. Therefore, our integrated diagnosis was astrocytoma, IDH mutation, WHO grade 2. Its molecular analyses include IDH1 R132H mutation and KIAA1549-BRAF fusion. After the operation, the patient did not receive chemo- or radiotherapy, and underwent an aggressive rehabilitation regiment. Follow up 10 months later, symptoms improved. To our best knowledge, this is the first case of concomitant IDH mutation and BRAF fusion in pediatric spinal cord astrocytoma.
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Astrocitoma/genética , Fusión Génica/genética , Isocitrato Deshidrogenasa/genética , Proteínas de la Membrana/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Médula Espinal/genética , Astrocitoma/diagnóstico por imagen , Astrocitoma/rehabilitación , Astrocitoma/cirugía , Niño , Humanos , Imagen por Resonancia Magnética , Masculino , Canal Medular/cirugía , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/rehabilitación , Neoplasias de la Médula Espinal/cirugía , Resultado del TratamientoRESUMEN
Dural plasmacytoma is a type of multiple myeloma of the central nervous system. Our patient presented with symptoms of headache. Imaging findings suspected glioblastoma, whereas pathological findings revealed mucosa-associated lymphoid tissue lymphoma associating with plasma cell differentiation. Further in-depth studies confirmed a diagnosis of dural plasmacytoma. This case indicates that morphological variations may occur in the extramedullary involvement of CD20-positive multiple myeloma. The multidisciplinary team contributes to the diagnosis of hematological diseases.
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Mieloma Múltiple/diagnóstico , Plasmacitoma/diagnóstico , Antineoplásicos/uso terapéutico , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Plasmacitoma/patologíaRESUMEN
AIMS: The aim of this study was to establish p53 immunohistochemistry (IHC) patterns to predict TP53 mutations in gastrointestinal neuroendocrine neoplasms (GI-NENs) and to determine whether p53 IHC patterns could be used for the differential diagnosis of neuroendocrine neoplasms. METHODS: TP53 gene sequencing and p53 IHC were performed on formalin-fixed paraffin-embedded (FFPE) tissue samples from 92 patients diagnosed with GI-NENs from five medical centers. RESULTS: The cohort included 35 well-differentiated neuroendocrine tumors and 57 poorly differentiated neuroendocrine carcinomas. Gene sequencing revealed 38 wild-type TP53 and 54 TP53 mutations. p53 expression was interpreted as follows: pattern A, p53 was absent from all tumor cells; pattern B, scattered and weak p53 expression in 1-20% of tumor cells; and pattern C was subclassified as pattern C1: variable p53 staining intensity in 21-60% of tumor cells and tumor cell nests with focal strong positive p53 staining and pattern C2: strong p53 staining in more than 60% of tumor cells. p53 IHC patterns were evaluated as a binary classifier where pattern B predicted wild-type TP53, and patterns A and C predicted TP53 mutations. The sensitivity, specificity, and overall accuracy of this binary classification to predict TP53 status were 0.963, 0.868, and 0.924, respectively. p53 IHC patterns were also correlated with TP53 mutation types. Most cases with pattern A harboured loss-of-function (LOF) mutations, whereas patterns B and C tended to indicate wild-type TP53 and gain-of-function (GOF) mutations, respectively. Furthermore, most of the well-differentiated NETs showed pattern B, whereas pattern C2 was more common in poorly differentiated NECs. Finally, staining interpretation between different observers also yielded high reproducibility. CONCLUSIONS: p53 IHC patterns may be used as predictors of TP53 gene mutations and therefore could be potential surrogate markers for TP53 mutations in GI-NENs and could distinguish between well-differentiated NETs and poorly differentiated NECs.
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Sculpting of structure and function of three-dimensional multicellular tissues depend critically on the spatial and temporal coordination of cellular physical properties, yet the organizational principles that govern these events, and their disruption in disease, remain poorly understood. Using a multicellular mammary cancer organoid model, here we map in three dimensions the spatial and temporal evolution of positions, motions, and physical characteristics of individual cells. Compared with cells in the organoid core, cells at the organoid periphery and the invasive front are found to be systematically softer, larger and more dynamic. These mechanical changes are shown to arise from supracellular fluid flow through gap junctions, suppression of which delays transition to an invasive phenotype. Together, these findings highlight the role of spatiotemporal coordination of cellular physical properties in tissue organization and disease progression.
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Encapsulated papillary carcinoma (EPC) of the breast is typically of low-to-intermediate grade (LTIG) with favorable prognosis. Rarely, high-grade (HG) EPC cases have been documented in recent years. Herein we compared the morphological, immunohistochemical, and clinical features of LTIG EPC to those of HG EPC. Of the 30 EPC patients, 25 were diagnosed as LTIG and five as HG (median age: 60 and 36 years, respectively); 80% of the HG EPCs exhibited predominantly solid architecture with prominent lymphoplasmacytic infiltrates, more crowded and thicker papillae, and greater stratification and irregular arrangement of malignant epithelial cells. Coexisting invasive components were observed in 32% and 80% of LTIG and HG cases, respectively. HG EPC was negative for hormone receptor staining. Additionally, 48% of LTIG EPC cases were moderately positive for human epidermal growth factor receptor 2 (Her-2) immunostaining (2+); among them, one case showed Her-2 gene amplification by fluorescence in situ hybridization. The basal-like markers cytokeratin 5/6 and epidermal growth factor receptor were detected in two and five HG cases, respectively. HG EPC was also characterized by a significantly high Ki-67 index (median: 85%, P<0.001). No local recurrence or distant metastasis was noted during the follow-up. HG EPC typically exhibited a solid architecture with a concurrent invasive component as well as a triple-negative and basal-like immunophenotype in young women. HG EPC might be indicative of high proliferative activity and potential aggressiveness.
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Neoplasias de la Mama/patología , Carcinoma Papilar/patología , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Femenino , Humanos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Supratentorial extraventricular ependymomas (STEEs) are relatively rare ependymomas, and their pathologic and genetic characteristics are still poorly understood. The aim of this study was to determine the histologic, immunohistochemical, and RELA fusion features, as well as to clarify in more detail the clinical courses of STEEs. Data from a total of 43 patients with STEEs was analyzed retrospectively. The status of RELA fusion was evaluated using fluorescence in situ hybridization. The expression levels of L1CAM, p65, cyclin D1, and p53 were assessed using immunohistochemistry. Progression-free survival and overall survival were calculated via Kaplan-Meier estimation using the log-rank test. Among all 43 STEEs, 65.1% (28/43) are positive for RELA fusion. Interestingly, almost half of the patients with RELA fusion-positive ependymomas are adults (13/28), and 89.3% (25/28) cases are anaplastic ependymomas, which suggests that RELA fusion testing is necessary in adults with STEEs. We investigated the immunohistochemical status of p65, L1CAM and CCND1 protein expression for their ability to predict RELA fusion status. RELA fusion-positive STEEs are frequently associated with expression of p65 (85.2%), L1CAM (85.2%), and CCND1 (81.5%). The accuracy of predicting RELA fusion status was much higher when the expression of p65 and L1CAM was combined, that is, when both were immunopositive. The status of RELA fusion, p53 overexpression, and extent of tumor resection are significantly associated with prognosis.