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Journal of the Egyptian National Cancer... Nov 2023Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive... (Review)
Review
BACKGROUND
Gestational Trophoblastic Neoplasia (GTN) is a disease of the reproductive age group with an incidence rate of <1% among all tumors involving the female reproductive tract. It occurs because of aberrant fertilization. Patients are diagnosed early because of aggravated symptoms during pregnancy. Moreover, patients also bleed from the tumor sites, which leads to early presentation. A cure rate of 100% can be achieved with adequate treatment.
MAIN BODY
In this literature review, the authors have brought to attention the risk factors, classification, and various treatment options in GTN patients according to their stratification as per the WHO scoring system. Patients are categorized into low and high risk based on the FIGO scoring system. Patients with low risk are treated with single-agent methotrexate or actinomycin-D. Despite the superiority of actinomycin-D in terms of efficacy, methotrexate remains the first choice of therapy in low-risk patients due to its better toxicity profile. Multi-agent chemotherapy with etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine (EMA-CO) leads to complete remission in 93% of high-risk GTN patients. Around 40% of patients with incomplete responses are salvaged with platinum-based multi-agent chemotherapy. Isolated chemo-resistant clones can be salvaged with surgical interventions.
CONCLUSION
The mortality in patients with GTN has significantly reduced over time. With adequate multi-disciplinary support, patients with GTN can ultimately be cured and can spend every day healthy reproductive life.
Topics: Pregnancy; Humans; Female; Dactinomycin; Methotrexate; Antineoplastic Combined Chemotherapy Protocols; Gestational Trophoblastic Disease; Etoposide; Cyclophosphamide; Vincristine; Retrospective Studies
PubMed: 38008872
DOI: 10.1186/s43046-023-00195-y -
American Journal of Clinical Pathology Nov 2020Soft tissue sarcomas are a group of tumors derived from the mesenchymal origin. Historically, they have been classified according to morphologic and immunohistochemical...
OBJECTIVES
Soft tissue sarcomas are a group of tumors derived from the mesenchymal origin. Historically, they have been classified according to morphologic and immunohistochemical characteristics. The advent of multiplexed next-generation sequencing (NGS), specifically RNA sequencing, has modified the classification of such tumors and others by determining categorization based on molecular alterations. The NUTM1 rearrangement, previously thought to be present only in carcinomas, has recently been reported in poorly differentiated high-grade sarcomas of the soft tissue. We present the first reported case of an epithelioid hyalinizing sarcoma harboring the MGA-NUTM1 fusion in an acral site.
METHODS
Histopathologic, immunohistochemical, and molecular testing were performed on resection tissue.
RESULTS
Histologically, the tumor showed an epithelioid morphology with prominent background hyalinization. Immunohistochemically, the tumor expressed CD99 and nuclear NUT-1. By NGS the tumor harbors MGA-NUTM1 fusion.
CONCLUSIONS
Our findings support more extensive use of NGS for accurate sarcoma classification and identification of potential therapeutic targets. Furthermore, they corroborate the fact that NUTM1-rearranged soft tissue tumors represent a spectrum of heterogeneous morphologic entities. This case also highlights the utility of NUT-1 immunohistochemical study as a possible screening tool for NUTM1-fused sarcomas.
Topics: Antineoplastic Combined Chemotherapy Protocols; Basic Helix-Loop-Helix Transcription Factors; Cyclophosphamide; Dactinomycin; Etoposide; Foot; Foot Bones; Gene Fusion; Humans; Hyalin; Ifosfamide; Magnetic Resonance Imaging; Male; Middle Aged; Muscle, Skeletal; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Nuclear Proteins; Organophosphorus Compounds; Sarcoma; Vincristine
PubMed: 32880623
DOI: 10.1093/ajcp/aqaa113 -
Journal of Clinical Oncology : Official... May 2023JCO The RMS2005 study included two phase III randomized trials for high-risk (HR) and observational trials for low (LR), standard (SR), and very high-risk (VHR)... (Clinical Trial)
Clinical Trial
JCO The RMS2005 study included two phase III randomized trials for high-risk (HR) and observational trials for low (LR), standard (SR), and very high-risk (VHR) patients who have been partially reported. Herein, we present a comprehensive report of results achieved for the complete unselected nonmetastatic cohort and analyze the evolution of treatment in comparison with previous European protocols. After a median follow-up of 73.1 months, the 5-year event-free survival (EFS) and overall survival (OS) of the 1,733 patients enrolled were 70.7% (95% CI, 68.5 to 72.8) and 80.4% (95% CI, 78.4 to 82.3), respectively. The results by subgroup: LR (80 patients) EFS 93.7% (95% CI, 85.5 to 97.3), OS 96.7% (95% CI, 87.2 to 99.2); SR (652 patients) EFS 77.4% (95% CI, 73.9 to 80.5), OS 90.6% (95% CI, 87.9 to 92.7); HR (851 patients) EFS 67.3% (95% CI, 64.0 to 70.4), OS 76.7% (95% CI, 73.6 to 79.4); and VHR (150 patients) EFS 48.8% (95% CI, 40.4 to 56.7), OS 49.7% (95% CI, 40.8 to 57.9). The RMS2005 study demonstrated that 80% of children with localized rhabdomyosarcoma could be long-term survivors. The study has established the standard of care across the European Soft tissue sarcoma Study Group countries with the confirmation of a 22-week vincristine/actinomycin D regimen for LR patients, the reduction of the cumulative ifosfamide dose in the SR group, and for HR disease, the omission of doxorubicin and the addition of maintenance chemotherapy.
Topics: Adolescent; Child; Humans; Antineoplastic Combined Chemotherapy Protocols; Dactinomycin; Disease-Free Survival; Rhabdomyosarcoma; Sarcoma
PubMed: 36848614
DOI: 10.1200/JCO.22.02093 -
Journal of Bioenergetics and... Aug 2022Circular RNAs (circRNAs) play vital roles in human diseases, including acute kidney injury (AKI). In this paper, we focused on the effect of circRNA zinc finger protein...
Circular RNAs (circRNAs) play vital roles in human diseases, including acute kidney injury (AKI). In this paper, we focused on the effect of circRNA zinc finger protein 644 (circZNF644) on AKI cell model progression. qRT-PCR was conducted for the levels of circZNF644, ZNF644, miR-140-5p and mixed lineage kinase domain like pseudokinase (MLKL). RNase R assay, actinomycin D assay and subcellular fraction analysis were conducted to analyze the features of circZNF644. CCK-8 assay and EdU assay were used to explore cell proliferation. Flow cytometry analysis was conducted to analyze cell cycle and cell apoptosis. Western blot assay was executed for protein levels. ELISA was performed for the levels of inflammatory cytokines. The relationships among circZNF644, miR-140-5p and MLKL were analyzed by dual-luciferase reporter assay and RIP assay. CircZNF644 was upregulated in LPS-stimulated HK-2 cells. LPS-mediated inhibitory effects on cell proliferation and cell cycle and promotional effects on apoptosis and inflammation were reversed by circZNF644 knockdown. CircZNF644 directly interacted with miR-140-5p and MLKL was the target gene of miR-140-5p. The impact of circZNF644 knockdown on HK-2 cell injury was relieved by miR-140-5p inhibition. Moreover, miR-140-5p enhancement alleviated LPS-triggered HK-2 cell damage, while MLKL elevation reversed the effect. CircZNF644 knockdown protected HK-2 cells from LPS-induced injury by altering miR-140-5p/MLKL pathway, suggesting that circZNF644 may be a hopeful therapeutic target for AKI.
Topics: Acute Kidney Injury; Apoptosis; Cell Proliferation; Cytokines; Dactinomycin; Humans; Lipopolysaccharides; MicroRNAs; Protein Kinases; RNA, Circular
PubMed: 35976517
DOI: 10.1007/s10863-022-09946-3 -
Bone Marrow Transplantation Nov 2021
Topics: Bridged Bicyclo Compounds, Heterocyclic; Dactinomycin; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Sulfonamides
PubMed: 34376805
DOI: 10.1038/s41409-021-01434-3 -
BJOG : An International Journal of... Aug 2020To find risk factors for second-line dactinomycin failure in patients with low-risk gestational trophoblastic neoplasia (GTN).
OBJECTIVE
To find risk factors for second-line dactinomycin failure in patients with low-risk gestational trophoblastic neoplasia (GTN).
DESIGN
Retrospective multicentre study.
SETTING
Tertiary reference centre.
POPULATION
Patients with low-risk GTN, treated with dactinomycin after methotrexate (MTX) failure.
METHODS
Retrospective analysis of 45 patients with low-risk GTN treated with dactinomycin after MTX failure, registered between 2006 and 2018.
MAIN OUTCOME MEASURES
Treatment outcome and risk factors for second-line dactinomycin failure.
RESULTS
Thirty patients (66.7%) were cured and 15 patients (33.3%) required third-line therapy. Type of antecedent pregnancy and hCG levels pre-dactinomycin were risk factors for failure in univariate analysis (odds ratio [OR] 19.30, 95% CI 2.04-182.60, P = 0.01 and OR 2.77, 95% CI 1.18-6.50, P = 0.02, respectively). Level of hCG pre-dactinomycin remained a significant risk factor in multivariate analysis (OR 2.93, 95% CI 1.02-8.40, P = 0.045). Complete remission (CR) was achieved in 83.3% of patients with pre-dactinomycin hCG levels <10 ng/ml, in 75% with hCG levels between 10 and 20 ng/ml, in 66.7% with hCG levels between 20 and 30 ng/ml, and in 50% with hCG levels between 30 and 40 ng/ml. No patients with hCG levels >40 ng/ml achieved CR. Patients with dactinomycin failure were treated surgically and/or with multi-chemotherapy; all except one achieved CR.
CONCLUSIONS
Treatment with dactinomycin after MTX failure in patients with low-risk GTN resulted in CR in 66.7%. Chance of curative treatment with dactinomycin is strongly related to the hCG level.
TWEETABLE ABSTRACT
Chance of curative treatment with dactinomycin after MTX failure in GTN patients is strongly related to the level of hCG pre-dactinomycin.
Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Chorionic Gonadotropin; Dactinomycin; Female; Gestational Trophoblastic Disease; Humans; Methotrexate; Middle Aged; Pregnancy; Retreatment; Retrospective Studies; Risk Factors; Treatment Failure; Young Adult
PubMed: 32141676
DOI: 10.1111/1471-0528.16198 -
Cancer Biotherapy & Radiopharmaceuticals Oct 2022Circular RNAs (circRNAs) have important roles in human malignancies, including breast cancer (BC). In this study, we explored the function of circRNA ribonuclease P RNA...
Circular RNAs (circRNAs) have important roles in human malignancies, including breast cancer (BC). In this study, we explored the function of circRNA ribonuclease P RNA component H1 (circ_RPPH1) in BC development and clarify the mechanistic pathway. Expression of circ_RPPH1, microRNA-542-3p (miR-542-3p), and Rho GTPase-activating protein 1 (ARHGAP1) in BC tissues and cells was determined by quantitative real-time polymerase chain reaction or Western blot assay. The stability of circ_RPPH1 was confirmed by RNase R and actinomycin D treatment. Cell viability and colony formation ability were measured by methyl thiazolyl tetrazolium (MTT) assay and colony formation assay, respectively. Western blot analysis was also used to detect proliferation biomarker (Ki67) and epithelial-mesenchymal transition (EMT) biomarkers (E-cadherin, N-cadherin, and vimentin). Flow cytometry and Transwell assays were performed to monitor cell apoptosis, migration, and invasion. The binding potency between miR-542-3p and circ_RPPH1 or ARHGAP1 was validated by dual-luciferase reporter assay. Functional role of circ_RPPH1 was investigated by xenograft tumor reporter assay. Upregulation of circ_RPPH1 and ARHGAP1, and downregulation of miR-542-3p were detected in BC tissues and cells. circ_RPPH1 knockdown or miR-542-3p introduction inhibited BC cell proliferation and metastasis, while promoted apoptosis . circ_RPPH1 sponged miR-542-3p to upregulate ARHGAP1 expression, thereby affecting BC progression. Moreover, depletion of circ_RPPH1 suppressed tumor growth . circ_RPPH1 contributed to BC tumorigenesis by sponging miR-542-3p and upregulating ARHGAP1, affording a novel mechanistic pathway in BC development.
Topics: Humans; Female; RNA, Circular; Vimentin; Ki-67 Antigen; Breast Neoplasms; Dactinomycin; Ribonuclease P; MicroRNAs; Cell Movement; Cell Proliferation; Cell Line, Tumor; Cadherins; GTPase-Activating Proteins
PubMed: 34402683
DOI: 10.1089/cbr.2020.4381 -
Experimental Cell Research Jan 2020The presence of elevated T lymphocytic microparticles (TLMPs) during respiratory illness is associated with airway and lung inflammation and epithelial injuries....
The presence of elevated T lymphocytic microparticles (TLMPs) during respiratory illness is associated with airway and lung inflammation and epithelial injuries. Although inflammasome and IL-1β signaling are crucial in airway inflammation, little was known about their regulatory mechanism. We hypothesized that TLMPs trigger inflammasome activation and IL-1β production in bronchial and alveolar epithelial cells to induce airway and lung inflammation. In this study, TLMPs induced IL-1β and IL-18 secretion through NLRP3 inflammasome activation and upregulated TLR4 mRNA and protein expression in alveolar (A549) and human airway epithelial (16HBE) cells. Pretreatment with CLI-095, a specific inhibitor of TLR4 signaling, dramatically diminished the TLMP-induced release of IL-1β and IL-18 by inhibiting the formation of NLRP3/ASC/pro-caspase-1 inflammasome in a dose-dependent manner. The TLMP-induced autophagy inhibition in epithelial cells was dependent on the PI3K/Akt signaling pathway, which significantly increased NLRP3 expression and enhanced TLMP-induced inflammation. TLR4, IL-1β, and IL-18 proteins harbored in TLMPs were nonessential for the pro-inflammatory effect. In conclusion, TLMPs induce bronchial and alveolar epithelial cell secretion of IL-1β and IL-18 cytokines by activating the TLR4 and PI3K/Akt signaling pathways and inhibiting autophagy. These effects lead to NLRP3 inflammasome formation and accumulation. TLMPs may be regarded as deleterious markers of airway and lung damage in respiratory diseases.
Topics: A549 Cells; Anti-Inflammatory Agents; Bronchi; CARD Signaling Adaptor Proteins; Caspase 1; Cell Line; Cell-Derived Microparticles; Culture Media, Conditioned; Dactinomycin; Epithelial Cells; Gene Expression Regulation; Humans; Inflammasomes; Inflammation; Interleukin-18; Interleukin-1beta; Lymphocytes; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sulfonamides; Toll-Like Receptor 4
PubMed: 31759058
DOI: 10.1016/j.yexcr.2019.111737 -
Disease Markers 2022To explore the role of circIFITM1 and its potential molecular mechanism in colon cancer.
OBJECTIVE
To explore the role of circIFITM1 and its potential molecular mechanism in colon cancer.
METHODS
The circIFITM1 in human samples and cell lines of colon cancer was measured via RT-PCR. The cyclicity of circIFITM1 was confirmed by agarose gel electrophoresis and Sanger sequencing, and the stability of circIFITM1 was confirmed by actinomycin D assay. The proliferative and invasive ability was detected by the CCK-8 assay and Transwell assay, respectively. RNA pull-down assay confirmed a combination of circIFITM1 and miRNA. Dual-luciferase reporter gene was used to detect the direct relationship between miRNA and the target gene.
RESULTS
circIFITM1 originated from the maternal gene IFITM1and had high stability. It was resistant to processing by actinomycin D. Upregulating circIFITM1 facilitated the proliferation and invasion of Lovo cells, while interfering with circIFITM1 expression inhibited them. circIFITM1 interacted with miR-802, and miR-802 targeted the 3'UTR of FOXP1. The overexpression of circIFITM1 downregulated miR-802 and upregulated FOXP1.
CONCLUSION
circIFITM1 facilitates the proliferative and invasive abilities via miR-802/FOXP1 in Lovo cells.
Topics: Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dactinomycin; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasm Invasiveness; Repressor Proteins; Transcription Factors
PubMed: 35783017
DOI: 10.1155/2022/7366337 -
Cancer Chemotherapy and Pharmacology Aug 2021Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of...
Actinomycin-D and vincristine are cytotoxic drugs commonly used to treat cancers in children. This prospective study assessed pharmacokinetic variability and toxicity of these drugs in children. Blood samples were collected in 158 patients. Actinomycin-D or vincristine concentrations were quantified using high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using non-compartmental methods. Target toxicities were collected prospectively. Actinomycin-D pharmacokinetics (n = 52 patients) were highly variable. The median (coefficient of variation, CV%) area under the concentration-time curve (AUC) was 332 ng/mL·h. (110%); clearance was 4.6 L/h/m (90%); half-life was 25 h (60%). No patient met the defined criteria for myelosuppression. In multivariate analysis, none of the demographic nor pharmacokinetic parameters was predictors of acute hepatotoxicity. Vincristine pharmacokinetics (n = 132 patients) demonstrated substantial variability. The median (CV%) AUC was 78 ng/mL·h (98%); clearance was 17.2 L/h/m (67%); half-life was 14.6 h (73%). In multivariate analysis, the effect of increasing age for a given BSA was an increase in neuropathy while the effect of increasing BSA for a given age was a decrease in neuropathy. Conclusion: Pharmacokinetics of both drugs were highly variable. For actinomycin-D, there was no correlation between demographic or pharmacokinetic parameters and target toxicities. For vincristine, the correlations of age and BSA and neuropathy are confounded by the correlation between age and BSA in children and the ability to ascertain neuropathy in infants. Variability may be attributed to dose reductions and capped doses for both drugs. Investigation of BSA-based dosing in young children is warranted to decrease variability of exposure.
Topics: Adolescent; Antineoplastic Agents; Area Under Curve; Child; Child, Preschool; Dactinomycin; Female; Half-Life; Humans; Infant; Male; Neoplasms; Prospective Studies; Vincristine
PubMed: 34023919
DOI: 10.1007/s00280-021-04295-1