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Article ; Online: Glioblastoma, IDH-Wildtype With Epithelioid Morphology and a

Umeres-Francia, Gianfranco E / Arias-Stella, Javier A / Manoukian, Saro / Arvanitis, Leonidas

International journal of surgical pathology

2024 , Page(s) 10668969241239679

Abstract: Glioblastoma, IDH-wildtype (GBM) is a high-grade astrocytic glioma that accounts for the majority of malignant brain tumors in adults. Within this entity, epithelioid GBM represents a histological subtype characterized by a loosely cohesive aggregate of ... ...

Abstract	Glioblastoma, IDH-wildtype (GBM) is a high-grade astrocytic glioma that accounts for the majority of malignant brain tumors in adults. Within this entity, epithelioid GBM represents a histological subtype characterized by a loosely cohesive aggregate of large cells with abundant cytoplasm, and vesicular nuclei that usually harbors the
Language	English
Publishing date	2024-04-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1336393-1
ISSN	1940-2465 ; 1066-8969
ISSN (online)	1940-2465
ISSN	1066-8969
DOI	10.1177/10668969241239679
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Article ; Online: Metastatic Testicular Sex Cord Tumor Harboring a

Carrillo-Ng, Hugo / Arvanitis, Leonidas / Manoukian, Saro / Arias-Stella, Javier A

International journal of surgical pathology

2023 , Page(s) 10668969231195043

Abstract: We present a case report of a 54-year-old male with a metastatic testicular sex cord tumor harboring ... ...

Abstract	We present a case report of a 54-year-old male with a metastatic testicular sex cord tumor harboring a
Language	English
Publishing date	2023-09-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	1336393-1
ISSN	1940-2465 ; 1066-8969
ISSN (online)	1940-2465
ISSN	1066-8969
DOI	10.1177/10668969231195043
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Article: A Case Report of Immunotherapy-Resistant MSI-H Gastric Cancer with Significant Intrapatient Tumoral Heterogeneity Characterized by Histologic Dedifferentiation.

Kethireddy, Nikhila / Arvanitis, Leonidas / LoBello, Janine / Woo, Yanghee / Szelinger, Szabolcs / Chao, Joseph

Journal of clinical medicine

2022 Volume 11, Issue 12

Abstract: We describe a patient with both gastric adenocarcinoma and metastatic squamous cell carcinoma (SCC) of unknown primary site. The possibility of a single malignant clonal process as opposed to differing primaries was supported by the finding of both ... ...

Abstract	We describe a patient with both gastric adenocarcinoma and metastatic squamous cell carcinoma (SCC) of unknown primary site. The possibility of a single malignant clonal process as opposed to differing primaries was supported by the finding of both histologies exhibiting high microsatellite instability. Despite evidence of tumor microsatellite instability, the patient's disease process did not respond to immune checkpoint inhibition. Our pursuit of whole-exome sequencing and comparing the single-nucleotide variant profiles of both tumors supported a single clonal process with the development of significant intratumoral heterogeneity. High intratumoral heterogeneity has posed a challenge to precision medicine approaches, but we also provide a review of the literature of this phenomenon mediating resistance to immunotherapy strategies.
Language	English
Publishing date	2022-06-14
Publishing country	Switzerland
Document type	Case Reports
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm11123413
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Article ; Online: Melanotic schwannoma: a case with strong CD34 expression, with histogenetic implications.

Arvanitis, Leonidas D

Pathology, research and practice

2010 Volume 206, Issue 10, Page(s) 716–719

Abstract: Melanotic schwannomas (MS) are rare tumors composed of cells with both schwannian and melanocytic features, which usually occur in the setting of Carney's Complex. We describe a case of a 36-year-old male who presented with a mass that was attached to ... ...

Abstract	Melanotic schwannomas (MS) are rare tumors composed of cells with both schwannian and melanocytic features, which usually occur in the setting of Carney's Complex. We describe a case of a 36-year-old male who presented with a mass that was attached to the vertebral body as well as the nerve roots of L2 and L3. Immunohistochemical positivity for S-100, HMB-45, and Pan-melanoma markers, as well as characteristic morphologic and ultrastructural findings, suggested that the lesion was a MS. The interest in this case lies in the fact that this case of MS showed strong CD34 expression, a marker that is generally negative in melanocytic tumors. We discuss the biologic significance of the high CD34 expression by the tumor cells and attempt to shed light on the histogenesis of this rare entity.
MeSH term(s)	Adult ; Antigens, CD34/analysis ; Humans ; Immunohistochemistry ; Male ; Melanins/analysis ; Microscopy, Electron ; Neurilemmoma/chemistry ; Neurilemmoma/genetics ; Neurilemmoma/pathology ; Neurilemmoma/surgery ; S100 Proteins/analysis ; Spinal Nerve Roots/chemistry ; Spinal Nerve Roots/pathology ; Spinal Nerve Roots/surgery
Chemical Substances	Antigens, CD34 ; Melanins ; S100 Proteins
Language	English
Publishing date	2010-10-15
Publishing country	Germany
Document type	Case Reports ; Journal Article
ZDB-ID	391889-0
ISSN	1618-0631 ; 0344-0338
ISSN (online)	1618-0631
ISSN	0344-0338
DOI	10.1016/j.prp.2010.02.011
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Article: Small Cell Lung Cancer Transformation following Treatment in EGFR-Mutated Non-Small Cell Lung Cancer.

Mambetsariev, Isa / Arvanitis, Leonidas / Fricke, Jeremy / Pharaon, Rebecca / Baroz, Angel R / Afkhami, Michelle / Koczywas, Marianna / Massarelli, Erminia / Salgia, Ravi

Journal of clinical medicine

2022 Volume 11, Issue 5

Abstract: EGFR-mutated lung adenocarcinoma patients who received tyrosine kinase inhibitors (TKIs) may initially respond to therapy, but over time, resistance eventually occurs. In a small population (5-10%), these patients can have a histological transformation ... ...

Abstract	EGFR-mutated lung adenocarcinoma patients who received tyrosine kinase inhibitors (TKIs) may initially respond to therapy, but over time, resistance eventually occurs. In a small population (5-10%), these patients can have a histological transformation to SCLC. Nine patients with EGFR-mutated lung adenocarcinoma who transformed to SCLC were evaluated at City of Hope. Patient clinical and pathology data, including multiple next-generation sequencing (NGS) results, clinical therapies, histology, and outcomes, were collected across multiple time points. Descriptive statistics were utilized to visualize and interpret the clinical therapeutic timeline and molecular transformation profiles for these patients. All patients received at least one line of EGFR TKI therapies prior to small cell lung cancer transformation, including erlotinib, afatinib, and osimertinib. Two patients also received chemotherapy prior to transformation (one with immunotherapy). The median months to small cell lung cancer transformation was 16 months, ranging from 4-49 months. The median overall survival (OS) was 29 months from diagnosis, with the minimum of 16 months and maximum of 62 months. The majority of patients had EGFR exon 19 deletion (
Language	English
Publishing date	2022-03-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm11051429
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Article ; Online: Transcription factor AP2 enhances malignancy of non-small cell lung cancer through upregulation of USP22 gene expression.

Sun, Ting / Zhang, Keqiang / Li, Wendong / Liu, Yunze / Pangeni, Rajendra P / Li, Aimin / Arvanitis, Leonidas / Raz, Dan J

Cell communication and signaling : CCS

2022 Volume 20, Issue 1, Page(s) 147

Abstract: Background: Ubiquitin-specific protease 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in various human cancers ... ...

Abstract	Background: Ubiquitin-specific protease 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in various human cancers including lung cancer. However, USP22 gene amplification seldom occurs, and the mechanism underlying USP22 upregulation in human cancers remains largely unknown. Methods: A luciferase reporter driven by a promoter region of USP22 gene was selectively constructed to screen against a customized siRNA library targeting 89 selected transcription factors to identify potential transcription factors (TFs) that regulate USP22 expression in human non-small cell lung cancers (NSCLC). Association of identified TFs with USP22 and potential role of the TFs were validated and explored in NSCLC by biological assays and immunohistochemistry analysis. Results: Luciferase reporter assays revealed that SP1 and activating transcription factor 3 (ATF3) inhibit USP22 transcription, while transcription factor AP-2 Alpha/Beta (TFAP2A/2B) and c-Myc promote USP22 transcription. Binding site-directed mutagenesis and chromosome immunoprecipitation (ChIP) assays validated AP2α and AP2β are novel TFs of USP22. Furthermore, overexpression of AP2A and AP2B significantly upregulates USP22 expression, and its target: Cyclin D1, concurrently enhances the proliferation, migration, and invasion of NSCLC A549 and H1299 cells in a partially USP22-dependent manner. Moreover, AP2 protein level correlated with USP22 protein in human NSCLC tissues. Conclusion: Our findings indicate AP2α and AP2β are important transcription factors driving USP22 gene expression to promote the progression of NSCLC, and further support USP22 as a potential biomarker and therapeutic target for lung cancer. Video Abstract.
MeSH term(s)	Activating Transcription Factor 3/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cyclin D1/metabolism ; Gene Expression ; Humans ; Luciferases/genetics ; Luciferases/metabolism ; Lung Neoplasms/pathology ; RNA, Small Interfering ; Thiolester Hydrolases/genetics ; Thiolester Hydrolases/metabolism ; Transcription Factor AP-2/genetics ; Transcription Factor AP-2/metabolism ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism ; Ubiquitin-Specific Proteases/genetics ; Ubiquitin-Specific Proteases/metabolism ; Up-Regulation/genetics
Chemical Substances	Activating Transcription Factor 3 ; RNA, Small Interfering ; TFAP2A protein, human ; Transcription Factor AP-2 ; Cyclin D1 (136601-57-5) ; Luciferases (EC 1.13.12.-) ; Thiolester Hydrolases (EC 3.1.2.-) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Ubiquitin-Specific Proteases (EC 3.4.19.12) ; Usp22 protein, human (EC 3.4.19.12)
Language	English
Publishing date	2022-09-19
Publishing country	England
Document type	Journal Article ; Video-Audio Media ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-022-00946-9
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Article: Predicting survival of NSCLC patients treated with immune checkpoint inhibitors: Impact and timing of immune-related adverse events and prior tyrosine kinase inhibitor therapy.

Sayer, Michael R / Mambetsariev, Isa / Lu, Kun-Han / Wong, Chi Wah / Duche, Ashley / Beuttler, Richard / Fricke, Jeremy / Pharoan, Rebecca / Arvanitis, Leonidas / Eftekhari, Zahra / Amini, Arya / Koczywas, Marianna / Massarelli, Erminia / Roosan, Moom Rahman / Salgia, Ravi

Frontiers in oncology

2023 Volume 13, Page(s) 1064169

Abstract: Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most ...

Abstract	Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Results: Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. Conclusion: The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.
Language	English
Publishing date	2023-02-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1064169
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Article ; Online: Inhibition of USP7 upregulates USP22 and activates its downstream cancer-related signaling pathways in human cancer cells.

Zhang, Keqiang / Sun, Ting / Li, Wendong / Guo, Yuming / Li, Aimin / Hsieh, Marcus / Wang, Jinghan / Wu, Jun / Arvanitis, Leonidas / Raz, Dan J

Cell communication and signaling : CCS

2023 Volume 21, Issue 1, Page(s) 319

Abstract: Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, ... ...

Abstract	Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, therapy resistance, and poor prognosis in many cancers. Although both DUBs are involved in the regulation of similar genes and signaling pathways, such as histone H2B monoubiquitination (H2Bub1), c-Myc, FOXP3, and p53, the interdependence of USP22 and USP7 expression has never been described. In the study, we found that targeting USP7 via either siRNA-mediated knockdown or pharmaceutical inhibitors dramatically upregulates USP22 in cancer cells. Mechanistically, the elevated USP22 occurs through a transcriptional pathway, possibly due to desuppression of the transcriptional activity of SP1 via promoting its degradation upon USP7 inhibition. Importantly, increased USP22 expression leads to significant activation of downstream signal pathways including H2Bub1 and c-Myc, which may potentially enhance cancer malignancy and counteract the anticancer efficacy of USP7 inhibition. Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of p53 tumor suppressor signaling pathway. In addition, USP22-Ko cancer cells are more sensitive to a combination of cisplatin and USP7 inhibitor. USP7 inhibitor treatment further suppresses in vivo angiogenesis and tumor growth and induced more apoptosis in USP22-Ko cancer xenografts. Taken together, our findings demonstrate that USP7 inhibition can dramatically upregulate USP22 in cancer cells; and targeting USP7 and USP22 may represent a more effective approach for targeted cancer therapy, which warrants further study. Video Abstract.
MeSH term(s)	Humans ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Specific Peptidase 7/metabolism ; Ubiquitin Thiolesterase/metabolism ; Lung Neoplasms/pathology ; Histones/metabolism ; Signal Transduction ; Cell Line, Tumor
Chemical Substances	Tumor Suppressor Protein p53 ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Histones ; USP7 protein, human (EC 3.4.19.12)
Language	English
Publishing date	2023-11-09
Publishing country	England
Document type	Video-Audio Media ; Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-023-01320-z
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Article ; Online: Asymptomatic diffuse "encephalitic" cerebral toxoplasmosis in a woman with systemic lupus erythematosus.

Murro, Diana / Novo, Jorge / Arvanitis, Leonidas

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia

2016 Volume 29, Page(s) 194–196

Abstract: Classic cerebral toxoplasmosis typically presents with neurologic symptoms such as seizures and mental status changes and histological examination shows focal lesions with necrosis. However, in the diffuse "encephalitic" form, patients are asymptomatic ... ...

Abstract	Classic cerebral toxoplasmosis typically presents with neurologic symptoms such as seizures and mental status changes and histological examination shows focal lesions with necrosis. However, in the diffuse "encephalitic" form, patients are asymptomatic with diffuse, inflammatory, non-necrotic lesions. Asymptomatic diffuse "encephalitic" toxoplasmosis has been reported only in four acquired immunodeficiency syndrome patients and one human immunodeficiency virus (HIV) negative patient with chronic lymphocytic leukemia. We present a 36-year-old HIV-negative woman with systemic lupus erythematosus and lupus nephritis who was on immunosuppression for 9years after cadaveric renal transplant and died from pulmonary hemorrhage and cytomegalovirus pneumonia. Brain autopsy findings revealed multifocal microglial nodules containing Toxoplasma bradyzoites and associated astrogliosis. These nodules were prominent in the cerebellum, midbrain and medulla and also present in the cortex and thalamus. No coagulative necrosis, necrotizing abscesses, or other opportunistic infections were present. The patient had previously exhibited no neurologic symptoms and there was no clinical suspicion for toxoplasmosis. To the best of our knowledge, this is the first case of diffuse, non-necrotizing, "encephalitic" cerebral toxoplasmosis reported in a lupus patient and also the first reported female case.
MeSH term(s)	Adult ; Autopsy ; Encephalitis/immunology ; Encephalitis/microbiology ; Fatal Outcome ; Female ; Humans ; Immunocompromised Host ; Kidney Transplantation ; Lupus Nephritis/complications ; Lupus Nephritis/immunology ; Opportunistic Infections/immunology ; Toxoplasmosis, Cerebral/immunology
Language	English
Publishing date	2016-07
Publishing country	Scotland
Document type	Case Reports ; Journal Article
ZDB-ID	1193674-5
ISSN	1532-2653 ; 0967-5868
ISSN (online)	1532-2653
ISSN	0967-5868
DOI	10.1016/j.jocn.2015.12.022
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Article ; Online: Correction: Protein Phosphatase 2A as a Therapeutic Target in Small Cell Lung Cancer.

Molecular cancer therapeutics

2024 Volume 21, Issue 4, Page(s) 700

Language	English
Publishing date	2024-04-04
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-22-0104
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