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Pediatric Blood & Cancer Mar 2021Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and...
BACKGROUND
Treatment of children and adolescents with alveolar rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been approached differently by North American and European cooperative groups. In order to define a better therapeutic strategy, we analyzed two studies conducted between 2005 and 2016 by the European paediatric Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group (COG).
METHODS
We retrospectively identified patients with ARMS N1 enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in RMS2005 comprised ifosfamide + vincristine + dactinomycin + doxorubicin (IVADo), IVA and maintenance (vinorelbine, cyclophosphamide); in ARST0531, it consisted of either vincristine + dactinomycin + cyclophosphamide (VAC) or VAC alternating with vincristine + irinotecan (VI). Local treatment was similar in both protocols.
RESULTS
The analysis of the clinical characteristics of 239 patients showed some differences between study groups: in RMS2005, advanced Intergroup Rhabdomyosarcoma Study Group (IRS) and large tumors predominated. There were no differences in outcomes between the two groups: 5-year event-free survival (EFS), 49% (95% confidence interval [CI]: 39-59) and 44% (95% CI: 30-58), and overall survival (OS), 51% (95% CI: 41-61) and 53.6% (95% CI: 40-68) in RMS2005 and ARST0531, respectively. In RMS2005, EFS of patients with FOXO1-positive tumors was significantly inferior to those with FOXO1-negative (49.3% vs 73%, P = .034). In contrast, in ARST0531, EFS of patients with FOXO1-positive tumors was 45% compared with 43.8% for those with FOXO1-negative.
CONCLUSIONS
The outcome of patients with ARMS N1 was similar in both protocols. However, patients with FOXO1 fusion-negative tumors enrolled in RMS2005 showed a significantly better outcome, suggesting that different strategies of chemotherapy may have an impact in the outcome of this subgroup of patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Lymph Nodes; Male; Prognosis; Retrospective Studies; Rhabdomyosarcoma, Alveolar; Survival Rate
PubMed: 33245207
DOI: 10.1002/pbc.28832 -
Efficacies of FAEV and EMA/CO regimens as primary treatment for gestational trophoblastic neoplasia.British Journal of Cancer Aug 2022Guidelines recommend etoposide, methotrexate, actinomycin D (EMA)/cyclophosphamide, vincristine (CO) as first-line treatment for high-risk gestational trophoblastic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Guidelines recommend etoposide, methotrexate, actinomycin D (EMA)/cyclophosphamide, vincristine (CO) as first-line treatment for high-risk gestational trophoblastic neoplasia (GTN). However, the floxuridine, actinomycin D, etoposide and vincristine (FAEV) regimen is commonly used to treat these patients in China. We conducted a randomised controlled trial to compare the efficacies and toxicities of FAEV and EMA/CO.
METHODS
Ninety-four patients with GTN were enrolled between May 2015 and April 2019 and randomly assigned to the FAEV or EMA/CO regimen. The rates of complete remission and relapse and the toxicities were compared in August 2021.
RESULTS
Five patients were excluded from the analysis. There were 46 patients in the FAEV group and 43 patients in the EMA/CO group. The complete remission rates following primary treatment were 89.1% and 79.1% (P = 0.193), respectively. The relapse rates were 8.7% and 9.3% (P = 0.604). The apparent incidences of grade 4 myelosuppression were 60.9% and 32.6% (P = 0.008), respectively; however, they became both 32.6% (P = 0.996) after granulocyte colony-stimulating factor support. Other adverse reactions were similar in the two groups. No patient died of disease.
CONCLUSION
FAEV has comparable efficacy and toxicity to EMA/CO as the primary treatment for high-risk GTN, and may thus be another first-line choice of chemotherapy.
CLINICAL TRIAL REGISTRATION
chictr.org.cn: ChiCTR1800017423.
Topics: Antineoplastic Combined Chemotherapy Protocols; Dactinomycin; Etoposide; Female; Floxuridine; Gestational Trophoblastic Disease; Humans; Neoplasm Recurrence, Local; Pregnancy; Vincristine
PubMed: 35459802
DOI: 10.1038/s41416-022-01809-3 -
Autopsy & Case Reports 2019Rhabdomyosarcoma (RMS) is a rare solid tumor in childhood and adolescence. The higher incidence is predominant during the first two decades of life. According to the...
Rhabdomyosarcoma (RMS) is a rare solid tumor in childhood and adolescence. The higher incidence is predominant during the first two decades of life. According to the Intergroup RMS Study Group, the embryonal RMS (ERMS), botryoidal variant, constitutes a histological subtype characterized as a "grape-like" lesion of 2.0 cm to 9.5 cm. The treatment involves chemotherapy, surgery, and/or radiotherapy. We present the case of a 14-year-old female patient diagnosed with ERMS, botryoidal variant, which originated in the uterine cervix with vaginal externalization. The initial therapeutic approach comprised an initial prolapsed mass excision followed by Wertheim-Meigs surgery due to the tumor extension. No consensual protocol to ERMS treatment is found in the medical literature; however, a combined approach seems to offer a better result. The postoperative time period was uneventful and the patient followed an adjuvant therapy with vincristine, d-actinomycin, and cyclophosphamide. A comprehensive evaluation of the therapeutic options preserving the reproductive function-unfortunately not always possible-is part of a multi-disciplined care team concerning the pediatric patients.
PubMed: 31372362
DOI: 10.4322/acr.2019.104 -
World Journal of Clinical Cases Sep 2022Rhabdomyosarcoma is a soft tissue tumor of primitive mesenchymal cells origin, occurring predominantly in children and adolescents, but extremely rare in adults and the...
BACKGROUND
Rhabdomyosarcoma is a soft tissue tumor of primitive mesenchymal cells origin, occurring predominantly in children and adolescents, but extremely rare in adults and the data regarding its treatment are sparse. Here, we would like to share our experience in the treatment of a locally advanced primary embryonal rhabdomyosarcoma of cervix in a 39-year-old female.
CASE SUMMARY
The patient was admitted with symptoms of intermenstrual bleeding and postcoital bleeding for six months. Physical examination revealed a friable, polyp-like mass (5 cm × 5 cm) in her cervix protruding into the vagina, while the uterus was mobile and normal-sized. Colposcopy-directed biopsy was performed, and a pathological diagnosis of embryonal rhabdomyosarcoma was made. Magnetic resonance imaging of the pelvis showed that the cervical volume was significantly increased, with a hypointense and hyperintense soft tissue mass on the right side, invading the cervical stroma; the mass was 5 cm × 5 cm with a clear boundary and confined to the cervix; there were no obvious findings indicating tumor invasion in the vaginal wall, parametrium, or pelvic wall; no enlarged lymph nodes were observed in the pelvic cavity. Based on our findings, the tumor was classified as stage IA according to the intergroup rhabdomyosarcoma studies criteria and IB3 stage according to The International Federation of Gynecology and Obstetrics 2018. The patient underwent two courses of neoadjuvant chemotherapy and a partial remission was achieved. Subsequently, she underwent laparoscopic radical hysterectomy, bilateral salpingo-oophrectomy and pelvic lymph node dissection and there were no risk factors revealed by postoperative pathological examination. Adjuvant chemotherapy was performed after surgery. The patient was disease-free until the last follow-up, 49 mo after completing the entire treatment.
CONCLUSION
Our experience suggests that neoadjuvant vincristine, dactinomycin, and cyclophosphamide chemotherapy followed by radical surgery and adjuvant chemotherapy might be reasonable therapeutic option for bulky cervical rhabdomyosarcoma in adults without fertility desire. Since large-scale studies on such rare conditions are rather impossible, further case reports and systematic reviews could help optimize the treatment of primary, bulky cervical rhabdomyosarcoma in adults.
PubMed: 36159439
DOI: 10.12998/wjcc.v10.i26.9454 -
BMC Cancer Oct 2021Actinomycin-D (Act-D) and Methotrexate (MTX) are both effective first-line agents for low-risk gestational trophoblastic neoplasia (LRGTN) with no consensus regarding... (Comparative Study)
Comparative Study Meta-Analysis
Direct comparisons of efficacy and safety between actinomycin-D and methotrexate in women with low-risk gestational trophoblastic neoplasia: a meta-analysis of randomized and high-quality non-randomized studies.
BACKGROUND
Actinomycin-D (Act-D) and Methotrexate (MTX) are both effective first-line agents for low-risk gestational trophoblastic neoplasia (LRGTN) with no consensus regarding which is more effective or less toxic. The primary objective of this meta-analysis is to compare Act-D with MTX in the treatment of LRGTN.
METHODS
We systematically searched electronic databases, conferences abstracts and trial registries for randomized controlled trials (RCTs) and high-quality non-randamized controlled trials (non-RCTs), comparing Act-D with MTX for patients with LRGTN. Studies were full-text screened for quality assessment and data extraction. Eligible studies must have reported complete remission rate. A fixed-effects meta-analysis was conducted to quantify the efficacy and safety of Act-D and MTX on odds ratios (ORs) and 95% confidence intervals (95%CIs), respectively.
RESULTS
A total of 8 RCTs and 9 non-RCTs (1674 patients) were included. In terms of efficacy, Act-D is superior to MTX in complete remission (80.2% [551/687] vs 65.1% [643/987]; OR 2.15, 95%CI 1.70 to 2.73). In the stratified analysis, patients from RCTs and non-RCTs both had a better complete remission from Act-D-based regimen (RCTs: 81.2% [259/319] vs 66.1% [199/301], OR 2.17, 95%CI 1.49 to 3.16; non-RCTs: 79.3% [292/368] vs 65.0% [444/686], OR 2.14, 95%CI 1.57 to 2.92). In terms of safety, patients receiving Act-D had higher risks of suffering nausea (OR 2.35, 95%CI 1.68 to 3.27), vomiting (OR 2.40, 95%CI 1.63 to 3.54), and alopecia (OR 2.76, 95%CI 1.60 to 4.75). Notably, liver toxicity (OR 0.38, 95%CI 0.19 to 0.76) was the only one that was conformed to have a higher risk for patients receiving MTX. In addition, the pooled results showed no significant difference of anaemia, leucocytopenia, neutropenia, thrombocytopnia, constipation, diarrhea, anorexia, and fatigue between Act-D and MTX.
CONCLUSIONS
Our meta-analysis suggests that Act-D had better efficacy profile in general, and MTX had less toxicities in LRGTN. Future clinical trials should be better orchestrated to provide more valid data on efficacy and toxicity.
Topics: Alopecia; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Chemical and Drug Induced Liver Injury; Dactinomycin; Female; Gestational Trophoblastic Disease; Humans; Methotrexate; Nausea; Pregnancy; Randomized Controlled Trials as Topic; Remission Induction; Risk; Treatment Outcome; Vomiting
PubMed: 34663255
DOI: 10.1186/s12885-021-08849-7 -
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 -
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 -
Investigative Ophthalmology & Visual... Feb 2024N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification catalyzed by N-acetyltransferase 10 (NAT10), a critical factor known to influence mRNA stability....
PURPOSE
N4-acetylcytidine (ac4C) is a post-transcriptional RNA modification catalyzed by N-acetyltransferase 10 (NAT10), a critical factor known to influence mRNA stability. However, the role of ac4C in visual development remains unexplored.
METHODS
Analysis of public datasets and immunohistochemical staining were conducted to assess the expression pattern of nat10 in zebrafish. We used CRISPR/Cas9 and RNAi technologies to knockout (KO) and knockdown (KD) nat10, the zebrafish ortholog of human NAT10, and evaluated its effects on early development. To assess the impact of nat10 knockdown on visual function, we performed comprehensive histological evaluations and behavioral analyses. Transcriptome profiling and real-time (RT)-PCR were utilized to detect alterations in gene expression resulting from the nat10 knockdown. Dot-blot and RNA immunoprecipitation (RIP)-PCR analyses were conducted to verify changes in ac4C levels in both total RNA and opsin mRNA specifically. Additionally, we used the actinomycin D assay to examine the stability of opsin mRNA following the nat10 KD.
RESULTS
Our study found that the zebrafish NAT10 protein shares similar structural properties with its human counterpart. We observed that the nat10 gene was prominently expressed in the visual system during early zebrafish development. A deficiency of nat10 in zebrafish embryos resulted in increased mortality and developmental abnormalities. Behavioral and histological assessments indicated significant vision impairment in nat10 KD zebrafish. Transcriptomic analysis and RT-PCR identified substantial downregulation of retinal transcripts related to phototransduction, light response, photoreceptors, and visual perception in the nat10 KD group. Dot-blot and RIP-PCR analyses confirmed a pronounced reduction in ac4C levels in both total RNA and specifically in opsin messenger RNA (mRNA). Additionally, by evaluating mRNA decay in zebrafish treated with actinomycin D, we observed a significant decrease in the stability of opsin mRNA in the nat10 KD group.
CONCLUSIONS
The ac4C-mediated mRNA modification plays an essential role in maintaining visual development and retinal function. The loss of NAT10-mediated ac4C modification results in significant disruptions to these processes, underlining the importance of this RNA modification in ocular development.
Topics: Humans; Animals; Acetyltransferases; Zebrafish; Dactinomycin; Opsins; Rod Opsins; RNA; RNA, Messenger
PubMed: 38381411
DOI: 10.1167/iovs.65.2.31 -
Frontiers in Oral Health Jun 2021Tumor angiogenesis is a hallmark of cancer. Therapeutic drug inhibitors targeting angiogenesis are clinically effective. We have previously identified GT198 (gene symbol...
Tumor angiogenesis is a hallmark of cancer. Therapeutic drug inhibitors targeting angiogenesis are clinically effective. We have previously identified GT198 (gene symbol also known as Hop2) as an oncoprotein that induces tumor angiogenesis in human cancers, including oral cancer. In this study, we show that the GT198 protein is a direct drug target of more than a dozen oncology drugs and several clinically successful anticancer herbs. GT198 is a DNA repair protein that binds to DNA. Using an DNA-binding assay, we tested the approved oncology drug set VII from the National Cancer Institute containing 129 oncology drugs. Identified GT198 inhibitors include but are not limited to mitoxantrone, doxorubicin, paclitaxel, etoposide, dactinomycin, and imatinib. Paclitaxel and etoposide have higher binding affinities, whereas doxorubicin has higher binding efficacy due to competitive inhibition. GT198 shares protein sequence homology with DNA topoisomerases, which are known drug targets, so that GT198 is likely a new drug target previously unrecognized. To seek more powerful GT198 inhibitors, we further tested several anticancer herbal extracts. The positive anticancer herbs with high affinity and high efficacy are all clinically successful ones, including allspice from Jamaica, or honey locust from China, and BIRM from Ecuador. Partial purification of allspice using an organic chemical approach demonstrated great feasibility of natural product purification, when the activity is monitored by the DNA-binding assay using GT198 as a target. Together, our study reveals GT198 as a new targeting mechanism for existing oncology drugs. The study also delivers an excellent drug target suitable for compound identification and natural product purification. In particular, this study opens an opportunity to rapidly identify drugs with high efficacy and low toxicity from nature.
PubMed: 34476412
DOI: 10.3389/froh.2021.679460