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1.
Transl Pediatr ; 13(4): 624-633, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38715664

ABSTRACT

Background: DICER1-associated tumors are heterogeneous and affect several organs. DICER1-associated primary intracranial sarcoma is associated with histone H3 trimethylation on lysine 27 (H3K27me3) loss in nucleus by immunohistochemistry. Methods: We explored the H3K27me3 immunostaining pattern in other DICER1-associated tumors. Twelve tumors from eleven patients with confirmed DICER1 mutations (sporadic and germline) data from a pancancer next-generation sequencing panel, and four tumors of pleuropulmonary blastoma (PPB) were retrieved from our database and stained with anti-H3K27me3 antibody. Results: The H3K27me3 expression in the nucleus showed heterogeneous mosaic loss in neoplastic Sertoli cell components in three of the five cases of moderately to poorly differentiated Sertoli-Leydig cell tumors. Among two tumors of DICER1-associated primary intracranial sarcoma, one showed complete loss of H3K27me3 in all neoplastic cells, whereas the other showed mosaic loss in the sarcomatous spindle cells. One DICER1-associated tumor with epithelial and mesenchymal differentiation, including pulmonary blastoma and PPB, showed mosaic loss of glandular epithelial and mesenchymal components. Four cases of type II PPB and a single case of type III PPB showed a similar mosaic loss of H3K27me3 staining restricted to large spindle cell components. All other components in all tumors-including Leydig cells; the areas of epithelial, cartilaginous, and rhabdomyomatous differentiation; and all cells of the remaining three cases (one papillary thyroid carcinoma and two cases of PPB type I)-demonstrated retained H3K27me3 staining. Conclusions: H3K27me3 expression is not universally lost in DICER1-associated tumors and thus is not predictive of DICER1 mutation status. The mosaic regional loss of H3K27me3 immunostaining is consistent in PPB type II and III, which can be a helpful diagnostic marker for these tumors and suggests a similarity to DICER1-associated intracranial sarcoma.

2.
J Hand Surg Glob Online ; 5(2): 242-245, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36974304

ABSTRACT

Cutis calcinosis of the hand in the setting of symbrachydactyly is presented in 2 unique patients. Both lesions were treated based on the standard of care protocols with resection of the calcified mass and hand reconstruction, as appropriate. The patients healed uneventfully without recurrence of the calcification at a the 1-year follow-up. The association between symbrachydactyly and calcinosis cutis is discussed along with a hypothesis on the pathophysiologic mechanism that could potentially explain this unusual occurrence and why it might be more common than previously identified.

3.
Int J Surg Pathol ; 30(3): 307-312, 2022 May.
Article in English | MEDLINE | ID: mdl-34488461

ABSTRACT

The small cell undifferentiated component of hepatoblastoma is an uncommon histologic component and is distinguished from small cell undifferentiated like pattern (originally called hepatoblastoma and now recognized to be malignant rhabdoid tumor) by the bi-allelic SMARCB1 mutations or copy number alterations in the latter. AT-rich interactive domain-containing protein 1A (ARID1A) is a part of the ATP-dependent switch/sucrose non-fermentable complex assembly, but mutations have not been reported as drivers of malignant rhabdoid tumor. ARID1A mutations in hepatocellular carcinoma are associated with poor prognosis but its significance in hepatoblastoma is unknown. We report a unique case of hepatoblastoma in a 19-month-old female with an unusual/atypical small cell undifferentiated component with ARID1A and beta-catenin mutations. It had an aggressive clinical course despite treatment, with metastases to the left psoas muscle, perihepatic and paratracheal lymph nodes, spinal cord, and leptomeninges. Leptomeningeal metastases resulted in diffuse cerebral edema and death. The initial diagnostic biopsy did not reveal rhabdoid cells while all metastatic foci showed cells with rhabdoid morphology in the autopsy specimens. Although this rhabdoid component resembled malignant rhabdoid tumor morphologically, molecular analyses failed to show mutations or deletions of SMARCB1.


Subject(s)
Hepatoblastoma , Liver Neoplasms , Rhabdoid Tumor , Biomarkers, Tumor/analysis , Child , DNA-Binding Proteins/genetics , Female , Hepatoblastoma/diagnosis , Hepatoblastoma/genetics , Humans , Immunohistochemistry , Infant , Liver Neoplasms/diagnosis , Liver Neoplasms/genetics , Mutation , Rhabdoid Tumor/diagnosis , Rhabdoid Tumor/genetics , Rhabdoid Tumor/pathology , Transcription Factors/genetics
5.
BMJ Case Rep ; 14(4)2021 Apr 15.
Article in English | MEDLINE | ID: mdl-33858888

ABSTRACT

Neurological complications of SARS-CoV-2 continue to be recognised. In children, neurological phenomenon has been reported generally in the acute infectious period. It is possible that SARS-CoV-2 could trigger an immune-mediated post-infectious phenomenon. Here, we present a unique case of post-infectious marantic cardiac lesion causing cerebrovascular accident in a patient with Down syndrome.


Subject(s)
COVID-19/complications , Down Syndrome , Nervous System Diseases/virology , Stroke/virology , Child , Down Syndrome/complications , Down Syndrome/virology , Humans , Inflammation/complications , Inflammation/virology
6.
Oncotarget ; 7(19): 27094-107, 2016 May 10.
Article in English | MEDLINE | ID: mdl-27027347

ABSTRACT

The signaling adaptor protein Crk has been shown to play an important role in various human cancers. However, its regulatory machinery is not clear. Here, we demonstrated that Crk induced EMT in A549 human lung adenocarcinoma cells through differential regulation of Rac1/Snail and RhoA/Slug, leading to decreased expression of E-cadherin and increased N-cadherin, fibronectin, and MMP2 expression. Cancer cells with mesenchymal features produced TGF-ß and also increased the levels of TGF-ß receptor. TGF-ß increased the endogenous levels of Crk and also augmented Crk-dependent expression of Snail and Slug, and conversely TGF-ß receptor inhibitor suppressed the levels of Snail and Slug. Overexpression of Crk was observed at the invasive front of human lung cancer tissues and was significantly associated with poor prognosis. Thus, TGF-ß and Crk collaborate to form a positive feedback loop to facilitate EMT, which may lead to the malignancy of human cancers possibly being affected by their microenvironment.


Subject(s)
Epithelial-Mesenchymal Transition/genetics , Lung Neoplasms/genetics , Proto-Oncogene Proteins c-crk/genetics , Signal Transduction/genetics , Transforming Growth Factor beta/genetics , A549 Cells , Animals , Base Sequence , Cell Line, Tumor , Cells, Cultured , Epithelial-Mesenchymal Transition/drug effects , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Proto-Oncogene Proteins c-crk/metabolism , Signal Transduction/drug effects , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/pharmacology , Transplantation, Heterologous
7.
Brain Tumor Pathol ; 31(2): 118-23, 2014 Apr.
Article in English | MEDLINE | ID: mdl-23979650

ABSTRACT

Small cell glioblastoma is a histological subtype of glioblastoma with characteristic features of highly proliferative, monotonous small glial cells with high nuclear cytoplasm ratio. Morphologically, malignant lymphoma or small cell metastatic carcinoma should be carefully discriminated. Some cases are difficult to differentiate from anaplastic oligodendroglioma. In this report, we present a case of small cell glioblastoma of an elderly man. The lack of IDH1/2 mutation was confirmed by immunohistochemistry and direct sequencing. Fluorescence in situ hybridization revealed the lower rates of chromosome 1p and 19q deletion. Microsatellite analysis disclosed partial 10q alteration near the PTEN locus. Not only morphological and immunohistochemical examinations, but also cytogenetical investigations for IDH1/2 mutation, 1p/19q loss, and PTEN alteration, are strongly supportive methods for the differential diagnosis of small cell glioblastoma and anaplastic oligodendroglioma.


Subject(s)
Brain Neoplasms/diagnosis , Glioblastoma/diagnosis , Aged , Biomarkers, Tumor/analysis , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , Diagnosis, Differential , Diffusion Magnetic Resonance Imaging , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence , Isocitrate Dehydrogenase/genetics , Male , Mutation , Oligodendroglioma/diagnosis , Oligodendroglioma/pathology , PTEN Phosphohydrolase/genetics
8.
Neuro Oncol ; 16(5): 671-85, 2014 May.
Article in English | MEDLINE | ID: mdl-24357458

ABSTRACT

BACKGROUND: Ionizing irradiation is an effective treatment for malignant glioma (MG); however, a higher rate of recurrence with more aggressive phenotypes is a vital issue. Although epithelial-mesenchymal transition (EMT) is involved in irradiation-induced cancer progression, the role for such phenotypic transition in MG remains unknown. METHODS: To investigate the mechanism of irradiation-dependent tumor progression in MG, we performed immunohistochemistry (IHC) and qRT-PCR using primary and recurrent MG specimens, MG cell lines, and primary culture cells of MG. siRNA technique was used for MG cell lines. RESULTS: In 22 cases of clinically recurrent MG, the expression of the mesenchymal markers vimentin and CD44 was found to be increased by IHC. In paired identical MG of 7 patients, the expression of collagen, MMPs, and YKL-40 were also elevated in the recurrent MGs, suggesting the The Cancer Genome Atlas-based mesenchymal subtype. Among EMT regulators, sustained elevation of Snail was observed in MG cells at 21 days after irradiation. Cells exhibited an upregulation of migration, invasion, numbers of focal adhesion, and MMP-2 production, and all of these mesenchymal features were abrogated by Snail knockdown. Intriguingly, phosphorylation of ERK1/2 and GSK-3ß were increased after irradiation in a Snail-dependent manner, and TGF-ß was elevated in both fibroblasts and macrophages but not in MG cells after irradiation. It was noteworthy that irradiated cells also expressed stemness features such as SOX2 expression and tumor-forming potential in vivo. CONCLUSIONS: We here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.


Subject(s)
Brain Neoplasms/metabolism , Epithelial-Mesenchymal Transition/radiation effects , Glioma/metabolism , Signal Transduction/radiation effects , Transcription Factors/metabolism , Animals , Cell Line, Tumor , Disease Progression , Female , Humans , Mice , Mice, Mutant Strains , Snail Family Transcription Factors
9.
Mol Cancer Ther ; 11(6): 1289-99, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22532597

ABSTRACT

Glioblastoma multiforme (GBM) is one of the most aggressive human tumors with a poor prognosis. Current standard treatment includes chemotherapy with the DNA-alkylating agent temozolomide concomitant with surgical resection and/or irradiation. However, a number of cases are resistant to temozolomide-induced DNA damage due to elevated expression of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Here, we show that upregulation of both MGMT and STAT3 was accompanied with acquisition of temozolomide resistance in the GBM cell line U87. Inactivation of STAT3 by inhibitor or short hairpin RNA (shRNA) downregulated MGMT expression in GBM cell lines. MGMT upregulation was not observed by the treatment of interleukin (IL)-6 which is a strong activator of STAT3. Contrarily, forced expressed MGMT could be downregulated by STAT3 inhibitor which was partially rescued by the proteasome inhibitor, MG132, suggesting the STAT3-mediated posttranscriptional regulation of the protein levels of MGMT. Immunohistochemical analysis of 44 malignant glioma specimens showed significant positive correlation between expression levels of MGMT and phosphorylated STAT3 (p-STAT3; P < 0.001, r = 0.58). Importantly, the levels of both MGMT and p-STAT3 were increased in the recurrence compared with the primary lesion in paired identical tumors of 12 cases. Finally, we showed that STAT3 inhibitor or STAT3 knockdown potentiated temozolomide efficacy in temozolomide-resistant GBM cell lines. Therefore, STAT3 inhibitor might be one of the candidate reagents for combination therapy with temozolomide for patients with temozolomide-resistant GBM.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Central Nervous System Neoplasms/drug therapy , DNA Modification Methylases/metabolism , DNA Repair Enzymes/metabolism , Dacarbazine/analogs & derivatives , Drug Resistance, Neoplasm , Glioblastoma/drug therapy , STAT3 Transcription Factor/antagonists & inhibitors , Tumor Suppressor Proteins/metabolism , Cell Line, Tumor/drug effects , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Dacarbazine/pharmacology , Down-Regulation , Drug Synergism , Gene Expression Regulation, Neoplastic/drug effects , Humans , RNA, Small Interfering/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Temozolomide , Tumor Suppressor Proteins/genetics
10.
Brain Tumor Pathol ; 28(1): 71-6, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21181449

ABSTRACT

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant tumor that mostly occurs in early childhood and has poor prognosis despite aggressive therapy. Adult cases are rare and, as far as we are aware, only 30 cases have been reported to date. Here we present the case of a 27-year-old female with left parietal AT/RT with the chief complaint of numbness of the right superior limb. First, the tumor was surgically removed and the diagnosis was grade II glioma. With additional radiotherapy, the clinical course after surgery was favorable. After 6 years, she had an operation for recurrence and the diagnosis was grade III glioma. Temozolomide was prescribed, and a disease-free period of 2 years followed. Surgery was performed for a third time for second recurrence with histology of diffuse growth of rhabdoid cells. Immunohistochemistry was partially positive for vimentin and epithelial membrane antigen. Ki-67 labeling index was extremely high and tumor cells showed no staining of INI1 suggestive of diagnosis of AT/RT. We re-evaluated past specimens and none had immunoreactivity of INI1. Ki-67 labeling index and O-6 methylguanine DNA methyltransferase (MGMT) staining were also re-examined and both increased gradually. She is still alive without recurrence for more than 1 year. As far as we are aware, this is the second longest survival of an adult with AT/RT.


Subject(s)
Biomarkers, Tumor/analysis , Brain Neoplasms/diagnosis , Disease-Free Survival , Parietal Lobe , Rhabdoid Tumor/diagnosis , Teratoma/diagnosis , Adult , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Chromosomal Proteins, Non-Histone/analysis , Combined Modality Therapy , DNA Modification Methylases/analysis , DNA Repair Enzymes/analysis , DNA-Binding Proteins/analysis , Dacarbazine/analogs & derivatives , Dacarbazine/therapeutic use , Female , Humans , Immunohistochemistry , Neoplasm Recurrence, Local , Neurosurgical Procedures , Rhabdoid Tumor/pathology , Rhabdoid Tumor/therapy , SMARCB1 Protein , Temozolomide , Teratoma/pathology , Teratoma/therapy , Time Factors , Transcription Factors/analysis , Tumor Suppressor Proteins/analysis
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