-
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 -
BMC Cancer Aug 2023Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various...
Comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for low-risk gestational trophoblastic neoplasia (FIGO Score 0-4): study protocol for a prospective, multicentre, randomized trial.
BACKGROUND
Single-agent chemotherapy using methotrexate or actinomycin D is the first-line treatment for patients with low-risk gestational trophoblastic neoplasia. Various methotrexate-based and actinomycin D-based single-agent regimens can be used. However, there is insufficient evidence to determine the superior regimen. To guide doctors in selecting a single-agent chemotherapy regimen for patients with low-risk gestational trophoblastic neoplasia, we will compare two regimens.
METHODS
We will conduct a multicentre, randomized, prospective clinical trial. Selected low-risk gestational trophoblastic neoplasia patients (FIGO score 0-4) will be randomized 1:1 to a biweekly single-dose actinomycin D group or a multiday methotrexate therapy group. The actinomycin D group will receive IV pulse actinomycin D (1.25 mg/m) every 14 days, and the methotrexate group will receive methotrexate (50 mg) intramuscularly on days 1, 3, 5, and 7 (4 doses per cycle) and leucovorin (15 mg) intramuscularly on days 2, 4, 6, and 8. This process will be repeated every 14 days. The primary endpoints will include the complete remission rate by single-agent therapy and the overall complete remission rate. The secondary endpoints will include the duration needed to achieve complete remission after single-agent chemotherapy, number of courses needed to achieve complete remission after single-agent chemotherapy, incidence and severity of adverse effects, effects on menstrual conditions and ovarian function based on the anti-Mullerian hormone level, and patient-reported quality of life.
DISCUSSION
Previous clinical trials comparing biweekly single-dose actinomycin D with multiday methotrexate therapy for treating low-risk gestational trophoblastic neoplasia patients failed to meet the expected case number. Through this multicentre study, the complete remission ratio and efficacy difference between biweekly single-dose actinomycin D and multiday methotrexate therapy will be obtained. This study will also provide the basis for formulating a preferred regimen for treating patients with low-risk gestational trophoblastic neoplasia.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT04562558, Registered on 13 September 2020 (Protocol version 2020-9-24, version 1.0).
Topics: Humans; Pregnancy; Female; Dactinomycin; Methotrexate; Prospective Studies; Quality of Life; Gestational Trophoblastic Disease; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37612621
DOI: 10.1186/s12885-023-11225-2 -
International Journal of Gynecological... Nov 2023International societies advocate for gestational trophoblastic neoplasia referral to designated expert centers. This study assessed the impact of centralization of...
OBJECTIVE
International societies advocate for gestational trophoblastic neoplasia referral to designated expert centers. This study assessed the impact of centralization of trophoblastic care on clinical outcomes.
METHODS
A centralized program was implemented in 2018 at two affiliated academic hospitals, Princess Margaret Cancer Center and Mount Sinai Hospital. A retrospective analysis of patients treated between 2000 and 2022 was performed and the clinical outcomes were compared before (2000-2017) and after (2018-2022) centralization. Statistical analyses were performed with significance set as p<0.05.
RESULTS
A total of 94 patients with trophoblastic neoplasia were included: 60 pre-centralization and 34 post-centralization, 79.8% low-risk and 18.1% high-risk. Centralization led to significant improvement for: (1) accurate score documentation (from 37.9% to 89.3%,); (2) contraception counseling (from 67.2% to 96.7%); (3) median time from diagnosis to chemotherapy (from 9 days to 1 day); and (4) incomplete follow-up (from 20.7% to 3.3%) (all p<0.05). First-line chemotherapy for low-risk neoplasia was dactinomycin in 47.9% and 87.0% pre- and post-centralization, respectively (p=0.005). The median number of chemotherapy cycles decreased from seven to four (p=0.01), and the median number of consolidation cycles increased from two to three (p<0.001). Serum human chorionic gonadotropin (hCG) levels of 10 000-100 000 IU/L were significantly associated with longer time to hCG normalization and higher risk of resistance to first-line chemotherapy compared with hCG levels <1000 IU/L.
CONCLUSION
Centralization of trophoblastic neoplasia care leads to greater guideline compliance, faster chemotherapy initiation, fewer chemotherapy cycles with optimized consolidation, and enhanced surveillance completion. This supports the establishment of trophoblastic neoplasia expert centers.
Topics: Pregnancy; Female; Humans; Retrospective Studies; Gestational Trophoblastic Disease; Chorionic Gonadotropin; Hydatidiform Mole; Uterine Neoplasms
PubMed: 37723102
DOI: 10.1136/ijgc-2023-004526 -
Pharmaceutical Development and... Dec 2022With the increase in respiratory conditions including lung cancer post covid-19 pandemic, drug-loaded nanoparticulate dry powder inhalers (DPIs) can facilitate targeted...
With the increase in respiratory conditions including lung cancer post covid-19 pandemic, drug-loaded nanoparticulate dry powder inhalers (DPIs) can facilitate targeted lung delivery as a patient-friendly, non-invasive method. The aim of this work was to synthesise and optimise iron oxide nanoparticles (IONPs) containing dactinomycin as a model drug, using Quality by Design principles. Chitosan and sodium alginate were investigated as polymeric coatings. The mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), burst-effect (BE), entrapment-efficiency and the emitted-dose (ED) were investigated in initial screening studies and outcomes used to set up a Design of Experiments. Results revealed that chitosan IONPs were superior to that of sodium alginate in delivering DPI with optimal properties [ED (89.9%), FPF (59.7%), MMAD (1.59 µm) and BE (12.7%)]. Design space for targeted IONPs included formulations containing 2.1-2.5% dactinomycin and 0.5-0.9% chitosan. Differential scanning calorimetry and X-ray diffraction and SEM-EDS analysis revealed effective formation of IONPs, and TEM images revealed the production of spherical IONPs with particle size of 4.4 ± 0.77 nm. This work overcame the light sensitivity of dactinomycin to potentially target the high molecular weight drugs to the lungs, with controlled delivery based on a reduced burst effect.
Topics: Humans; Administration, Inhalation; Alginates; Chitosan; COVID-19; Dactinomycin; Lung; Lung Neoplasms; Nanoparticles; Respiratory Aerosols and Droplets; Drug Delivery Systems
PubMed: 36416448
DOI: 10.1080/10837450.2022.2152047 -
Journal of Integrative Bioinformatics Sep 2022Breast cancer metastases are most commonly found in bone, an indication of poor prognosis. Pathway-based biomarkers identification may help elucidate the cellular...
Breast cancer metastases are most commonly found in bone, an indication of poor prognosis. Pathway-based biomarkers identification may help elucidate the cellular signature of breast cancer metastasis in bone, further characterizing the etiology and promoting new therapeutic approaches. We extracted gene expression profiles from mouse macrophages from the GEO dataset, GSE152795 using the GEO2R webtool. The differentially expressed genes (DEGs) were filtered by log2 fold-change with threshold 1.5 (FDR < 0.05). STRING database and Enrichr were used for GO-term analysis, miRNA and TF analysis associated with DEGs. Autodock Vienna was exploited to investigate interaction of anti-cancer drugs, Actinomycin-D and Adriamycin. Sensitivity and specificity of DEGs was assessed using receiver operating characteristic (ROC) analyses. A total of 61 DEGs, included 27 down-regulated and 34 up-regulated, were found to be significant in breast cancer bone metastasis. Major DEGs were associated with lipid metabolism and immunological response of tumor tissue. Crucial DEGs, Bcl3, ADGRG7, FABP4, VCAN, and IRF4 were regulated by miRNAs, miR-497, miR-574, miR-138 and TFs, CCDN1, STAT6, IRF8. Docking analysis showed that these genes possessed strong binding with the drugs. ROC analysis demonstrated Bcl3 is specific to metastasis. DEGs Bcl3, ADGRG7, FABP4, IRF4, their regulating miRNAs and TFs have strong impact on proliferation and metastasis of breast cancer in bone tissues. In conclusion, present study revealed that DEGs are directly involved in of breast tumor metastasis in bone tissues. Identified genes, miRNAs, and TFs can be possible drug targets that may be used for the therapeutics. However, further experimental validation is necessary.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Computational Biology; Dactinomycin; Doxorubicin; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Interferon Regulatory Factors; Mice; MicroRNAs; Neoplasms
PubMed: 35388653
DOI: 10.1515/jib-2021-0041 -
Environmental Pollution (Barking, Essex... Nov 2022Environmental cadmium (Cd) or high-fat diet (HFD) exposure alone are risk factors of male infertility. However, the effect and mechanism of co-exposure to HFD and Cd on...
Environmental cadmium (Cd) or high-fat diet (HFD) exposure alone are risk factors of male infertility. However, the effect and mechanism of co-exposure to HFD and Cd on sperm quality remain unclear. This study was aimed to explore the combined effects of HFD and Cd on spermatogenesis as well as its m6A-dependent mechanism in vivo and in vitro. As a result, co-exposure of HFD and Cd resulted in a significant decrease in the number of mature testicular seminiferous tubules and epididymis sperm quantity in mice, compared with Cd or HFD exposure alone. Correspondingly, the mRNAs expression of Smc3(spermatocytes marker), Acrv1(round spermatids marker) and Lzumo3(elongated spermatids marker) were downregulated in HFD and Cd group. Furthermore, combined exposure downregulated the expression of meiosis-related proteins (STRA8 and SYCP3), increased the m6A level of Stra8, and upregulated the expression of m6A-related proteins (METTL3 and YTHDF2) in mouse spermatocytes. Mechanistically, the above-mentioned impacts caused by co-exposure were markedly restored by Mettl3 siR and Ythdf2 siR. In addition, RNA stability assay showed that Ythdf2 siR obviously reversed co-exposure-increased Stra8 mRNA degradation rate in actinomycin-D-treated mouse spermatocytes. Meanwhile, excess ROS was observed in combined-exposure group, and a free radical scavenger N-tert-Butyl-α-phenylnitrone (PBN) attenuated co-exposure-upregulated expression of METTL3 and YTHDF2 in mouse spermatocytes. These results suggested that combination of HFD and Cd impaired spermatogenesis by degrading Stra8 in an m6A-YTHDF2-dependent manner via ROS activation.
Topics: Animals; Cadmium; Dactinomycin; Diet, High-Fat; Free Radical Scavengers; Male; Membrane Proteins; Mice; Reactive Oxygen Species; Semen; Spermatogenesis; Transcription Factors
PubMed: 36084736
DOI: 10.1016/j.envpol.2022.120112 -
Biochemical and Biophysical Research... Jan 2022Actinomycin D has been reported to selectively inhibit rRNA synthesis and ribosome biogenesis, induce G2 checkpoint of cell cycle arrest in HeLa cells. In Arabidopsis,...
Actinomycin D has been reported to selectively inhibit rRNA synthesis and ribosome biogenesis, induce G2 checkpoint of cell cycle arrest in HeLa cells. In Arabidopsis, actinomycin D was also used as agent to preferentially inhibit the ribosome biosynthesis and ribosomal function. However, the function of actinomycin D on Arabidopsis root development remains to be elucidated. In this study, we exposed Arabidopsis seedlings to actinomycin D with the aim of evaluating the effects of ribosome biogenesis on root development. The results demonstrated that actinomycin D inhibited Arabidopsis root growth by reduced meristematic activity in a dose dependent manner. Exposure to actinomycin D decreased the expression of WOX5 and key stem cell niche-defining transcription factors SHR and PLT1, thus the loss function of QC identity and stem cell niche maintenance. In addition, dead cells were observed after actinomycin D treatment in root stele initials and DNA damage response was constitutively activated. Collectively, we propose that ribosome biogenesis plays key role in primary root growth through maintenance of root stem cell niche and DNA damage response in Arabidopsis.
Topics: Arabidopsis; Arabidopsis Proteins; Cell Death; DNA Damage; Dactinomycin; Indoleacetic Acids; Meristem; Organ Size; Organelle Biogenesis; Plant Roots; Ribosomes; Stem Cell Niche
PubMed: 34952471
DOI: 10.1016/j.bbrc.2021.12.030 -
Journal of Proteins and Proteomics 2021Outbreak of COVID-19 by SARS-CoV-2 infection caused severe acute respiratory syndrome that has been declared a public health emergency of international concern. To...
Outbreak of COVID-19 by SARS-CoV-2 infection caused severe acute respiratory syndrome that has been declared a public health emergency of international concern. To control infections, there is urgent need to develop an effective therapeutic strategy. COVID-19 viral spike glycoprotein and proteases play major role in viral entry and mediating virus replication and spread and thus can serve as potential antiviral drug target. Being highly specific, efficacious and safe, peptides hold their place in therapeutics. In present study, molecular docking of 21 pharmacologically active non ribosomal peptides (NRPs) from marine microbes with SARS-CoV-2 spike glycoprotein and papain such as protease was done. Dactinomycin, Tyrocidine A and Gramicidin S showed highest binding interaction with target proteins. The binding affinity of Dactinomycin and Gramicidin S docked with SARS-CoV-2 spike glycoprotein was - 12.4 kcal/mol and - 11.4 kcal/mol, respectively. This suggested their potential to destabilize SARS spike protein binding with human host ACE2 receptor and thus hindering viral entry to the cells. Binding affinity of Tyrocidine A and Gramicidin S with SARS-CoV-2 papain-like protease was - 13.1 kcal/mol and - 11.4 kcal/mol, respectively which might be inhibited COVID-19 by acting on the protease. Gramicidin S showed same binding affinity for both target proteins and thus expected to be most potent. Based on the binding energy score, it was suggested that these pharmacologically active NRPs are potential molecules to be tested against SARS-CoV-2 and used to develop effective antiviral drugs.
PubMed: 34456530
DOI: 10.1007/s42485-021-00072-z -
Surgical Oncology Sep 2021Locoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be...
BACKGROUND AND OBJECTIVES
Locoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be considered in affected patients. In the present study, we have analyzed the results of HILPs performed in our department.
PATIENTS AND METHODS
Eighty patients with locoregional metastases of the extremities received HILP at the Department of Surgery between January 2007 and December 2016. The mean follow-up was 38 months.
RESULTS
The study included 50 men and 30 women (mean age: 63 years). The median time between melanoma diagnosis and HILP was 25 months (range: 1-219 months). HILP was performed in curative (n = 45) and palliative (n = 35) intention. Seventy-five patients received a drug combination of melphalan/dactinomycin and five patients received a drug combination of melphalan/tumor necrosis factor-alpha. Remission rates were determined in 72 of 80 patients (90%) as follows: partial response n = 28, complete response n = 25, no response n = 19. Of the 25 patients with complete response, 13 patients developed a new tumor manifestation during follow-up (locoregional recurrences n = 4; distant metastases n = 3; both n = 6). The median overall survival rate was 33 months. Tumor stage influenced the survival rate significantly (p = 0.001). Patients with complete response showed a significantly better overall survival than patients with partial or no response (p = 0.016).
CONCLUSION
HILP is an effective therapeutic option in patients with locoregional metastases. This procedure carries a certain risk of side effects and adverse events but overall results in good response rates. Therefore, HILP should be offered to selected patients based on an individual discussion, considering their health status and oncological prognosis.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Prognosis; Retrospective Studies; Survival Rate; Young Adult
PubMed: 33992896
DOI: 10.1016/j.suronc.2021.101603 -
Scientific Reports Aug 2020Although many advances have been achieved to treat aggressive tumours, cancer remains a leading cause of death and a public health problem worldwide. Among the main...
Although many advances have been achieved to treat aggressive tumours, cancer remains a leading cause of death and a public health problem worldwide. Among the main approaches for the discovery of new bioactive agents, the prospect of microbial secondary metabolites represents an effective source for the development of drug leads. In this study, we investigated the actinobacterial diversity associated with an endemic Antarctic species, Deschampsia antarctica, by integrated culture-dependent and culture-independent methods and acknowledged this niche as a reservoir of bioactive strains for the production of antitumour compounds. The 16S rRNA-based analysis showed the predominance of the Actinomycetales order, a well-known group of bioactive metabolite producers belonging to the Actinobacteria phylum. Cultivation techniques were applied, and 72 psychrotolerant Actinobacteria strains belonging to the genera Actinoplanes, Arthrobacter, Kribbella, Mycobacterium, Nocardia, Pilimelia, Pseudarthrobacter, Rhodococcus, Streptacidiphilus, Streptomyces and Tsukamurella were identified. The secondary metabolites were screened, and 17 isolates were identified as promising antitumour compound producers. However, the bio-guided assay showed a pronounced antiproliferative activity for the crude extracts of Streptomyces sp. CMAA 1527 and Streptomyces sp. CMAA 1653. The TGI and LC values revealed the potential of these natural products to control the proliferation of breast (MCF-7), glioblastoma (U251), lung/non-small (NCI-H460) and kidney (786-0) human cancer cell lines. Cinerubin B and actinomycin V were the predominant compounds identified in Streptomyces sp. CMAA 1527 and Streptomyces sp. CMAA 1653, respectively. Our results suggest that the rhizosphere of D. antarctica represents a prominent reservoir of bioactive actinobacteria strains and reveals it as an important environment for potential antitumour agents.
Topics: Actinobacteria; Actinomycetales; Antarctic Regions; Anthracyclines; Antineoplastic Agents; Biological Factors; Cell Line, Tumor; Cell Proliferation; Culture Techniques; Dactinomycin; Drug Discovery; Humans; Neoplasms; Streptomyces
PubMed: 32807803
DOI: 10.1038/s41598-020-69786-2