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Journal of Oncology Pharmacy Practice :... Jul 2022Medication errors are avoidable occurrences that can assume clinically significant dimensions and impose relevant costs to the health system, especially in the context... (Review)
Review
BACKGROUND
Medication errors are avoidable occurrences that can assume clinically significant dimensions and impose relevant costs to the health system, especially in the context of antineoplastic therapy.
OBJECTIVE
Assess the clinical significance and economic impacts of a clinical pharmaceutical service. This retrospective study consists of an analysis of pharmacy interventions and drug-related problems found in a review of electronic prescriptions referring to antineoplastic therapy of a public teaching tertiary hospital in Brazil.
METHOD
Retrospective descriptive study obtained from electronic records of drug-related problems and pharmaceutical interventions related to antineoplastic therapy for oncological and hematological diseases, obtained through the pharmacotherapy review service. The accepted interventions were analyzed for the financial impact generated, evaluating your direct costs. The perception of clinical significance of a random sample of interventions was ascertained by the experts' opinion, using the Delphi method.
RESULTS
The most frequent problem was a "lack of information to professionals" (25.06%), "problems as to the frequency and interval of doses" (22.90%), and "medication underdosing" (16.20%). Dose adjustment (31.50%) and clarifications (30.90%) were the most frequent pharmaceutical interventions. In the second round of Delphi, experts rated 77.77% of interventions as extremely significant and very significant. The main drugs reported in the interventions were cyclophosphamide, carboplatin, methotrexate, folinic acid, and monoclonal antibodies. The savings amounted to US$1,193,970.18 and involved mainly bortezomib, dactinomycin, and monoclonal antibodies.
CONCLUSION
Clinical pharmacy services contributed to the rational use of medicines presenting clinical significance and avoiding waste of financial resources.
Topics: Humans; Retrospective Studies; Pharmacy Service, Hospital; Tertiary Care Centers; Brazil; Antineoplastic Agents; Pharmaceutical Preparations; Pharmacists
PubMed: 34000918
DOI: 10.1177/10781552211017650 -
International Journal of Cancer May 2021High-risk gestational trophoblastic neoplasia (GTN) is highly chemosensitive with an excellent prognosis with treatment. Historically in the United Kingdom, the...
M-EA (methotrexate, etoposide, dactinomycin) and EMA-CO (methotrexate, etoposide, dactinomycin / cyclophosphamide, vincristine) regimens as first-line treatment of high-risk gestational trophoblastic neoplasia.
High-risk gestational trophoblastic neoplasia (GTN) is highly chemosensitive with an excellent prognosis with treatment. Historically in the United Kingdom, the high-risk regimens used have been M-EA (methotrexate, etoposide, dactinomycin) (Sheffield) and EMA-CO (methotrexate, etoposide, dactinomycin / cyclophosphamide, vincristine) (Charing Cross, London) with prior published data suggesting no difference in survival between these. Our Sheffield treatment policy changed in 2014, switching from M-EA to EMA-CO, aiming to reduce time in hospital, and harmonise UK practice. We aimed to report the toxicities, response rates and survival outcomes for 79 patients with high-risk GTN treated in the first-line setting with either M-EA (n = 59) or EMA-CO (n = 20) from 1998 to 2018. Median duration of treatment was similar (M-EA, 17.3 weeks (IQR 13.9-22.6) and 17.6 weeks (IQR 13.4-20.7) with EMA-CO. For M-EA, overall human chorionic gonadotrophin (hCG) complete response (CR) rate was 84.7% (n = 50/59). Two patients died of drug-resistant disease after several lines of multiagent chemotherapy; overall survival is 96.6% (median follow-up 10.4 years). For EMA-CO, overall hCG CR rate was 70%, overall survival is 100% (median follow-up 4 years). In our experience, patients treated with EMA-CO experienced an apparent increased incidence of neutropenia, non-neutropenic Grade 3-4 infection, peripheral neuropathy and more treatment delays and nights in hospital. Granulocyte-colony stimulating factor, after both EMA and CO arms, titrated to baseline neutrophil count improved the toxicity profile. Both treatment regimens are associated with excellent prognosis; selection of regimen may be further guided by individual patients' personal, social and family circumstances. There is further rationale to explore whether these regimens can be refined, such as 2-weekly EMA, to optimise patient experience and reduce toxicity while maintaining efficacy.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dactinomycin; Etoposide; Female; Gestational Trophoblastic Disease; Humans; Methotrexate; Pregnancy; Risk Factors; Vincristine
PubMed: 33210289
DOI: 10.1002/ijc.33403 -
BJOG : An International Journal of... Apr 2023High-risk gestational trophoblastic neoplasia (GTN) is rare and treated with diverse approaches. Limited published institutional data has yet to be systematically... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
High-risk gestational trophoblastic neoplasia (GTN) is rare and treated with diverse approaches. Limited published institutional data has yet to be systematically reviewed.
OBJECTIVES
To compile global high-risk GTN (prognostic score ≥7) cohorts to summarise treatments and outcomes by disease characteristics and primary chemotherapy.
SEARCH STRATEGY
MEDLINE, Embase, Scopus, ClinicalTrials.gov and Cochrane were searched through March 2021.
SELECTION CRITERIA
Full-text manuscripts reporting mortality among ≥10 high-risk GTN patients.
DATA COLLECTION AND ANALYSIS
Binomial proportions were summed, and random-effects meta-analyses performed.
MAIN RESULTS
From 1137 records, we included 35 studies, representing 20 countries. Among 2276 unique high-risk GTN patients, 99.7% received chemotherapy, 35.8% surgery and 4.9% radiation. Mortality was 10.9% (243/2236; meta-analysis: 10%, 95% confidence interval [CI] 7-12%) and likelihood of complete response to primary chemotherapy was 79.7% (1506/1890; meta-analysis: 78%, 95% CI: 74-83%). Across 24 reporting studies, modern preferred chemotherapy (EMA/CO or EMA/EP) was associated with lower mortality (overall: 8.8 versus 9.5%; comparative meta-analysis: 8.1 versus 12.4%, OR 0.42, 95% CI: 0.20-0.90%, 14 studies) and higher likelihood of complete response (overall: 76.6 versus 72.8%; comparative meta-analysis: 75.9 versus 60.7%, OR 2.98, 95% CI: 1.06-8.35%, 14 studies), though studies focused on non-preferred regimens reported comparable outcomes. Mortality was increased for ultra-high-risk disease (30 versus 7.5% high-risk; meta-analysis OR 7.44, 95% CI: 4.29-12.9%) and disease following term delivery (20.8 versus 7.3% following molar pregnancy; meta-analysis OR 2.64, 95% CI: 1.10-6.31%). Relapse rate estimates ranged from 3 to 6%.
CONCLUSIONS
High-risk GTN is responsive to several chemotherapy regimens, with EMA/CO or EMA/EP associated with improved outcomes. Mortality is increased in patients with ultra-high-risk, relapsed and post-term pregnancy disease.
Topics: Pregnancy; Female; Humans; Methotrexate; Dactinomycin; Neoplasm Recurrence, Local; Gestational Trophoblastic Disease; Hydatidiform Mole; Retrospective Studies
PubMed: 36648416
DOI: 10.1111/1471-0528.17374 -
International Journal of Molecular... Apr 2020In this study we explored the efficacy of combining low dose photodynamic therapy using a porphyrin photosensitiser and dactinomycin, a commonly used chemotherapeutic...
In this study we explored the efficacy of combining low dose photodynamic therapy using a porphyrin photosensitiser and dactinomycin, a commonly used chemotherapeutic agent. The studies were carried out on compressed collagen 3D constructs of two human ovarian cancer cell lines (SKOV3 and HEY) versus their monolayer counterparts. An amphiphilc photosensitiser was employed, disulfonated tetraphenylporphine, which is not a substrate for ABC efflux transporters that can mediate drug resistance. The combination treatment was shown to be effective in both monolayer and 3D constructs of both cell lines, causing a significant and synergistic reduction in cell viability. Compared to dactinomycin alone or PDT alone, higher cell kill was found using 2D monolayer culture vs. 3D culture for the same doses. In 3D culture, the combination therapy resulted in 10 and 22 times higher cell kill in SKOV3 and HEY cells at the highest light dose compared to dactinomycin monotherapy, and 2.2 and 5.5 times higher cell kill than PDT alone. The combination of low dose PDT and dactinomycin appears to be a promising way to repurpose dactinomycin and widen its therapeutic applications.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Dactinomycin; Female; Humans; Ovarian Neoplasms; Photochemotherapy
PubMed: 32366058
DOI: 10.3390/ijms21093203 -
Cell Discovery 2020Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead...
Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV-host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the "" pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.
PubMed: 32194980
DOI: 10.1038/s41421-020-0153-3 -
Environmental Toxicology Mar 2024Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients.
BACKGROUND
Gastric cancer is the most common malignant tumour of the digestive system, yet there is a lack of reported prognostic biomarkers for STAD patients.
METHODS
Transcriptomic expression data of STAD from GEO database, single cell sequencing data from OMIX gastric cancer database. Conservative molecular typing of gastric cancer was constructed using non-negative matrix factorization (NMF). The abundance of 28 immune cells in the tumour samples was assessed using ssGSEA. The R package "oncoPredict" was used to predict chemotherapy response. TIDE website for immunotherapy response prediction. Finally, single cell analysis was performed to clarify the specific type annotation of STAD cells and to analysis their spatial expression.
RESULTS
Hypoxia-score demonstrated excellent prognostic discrimination in TCGA gastric cancer samples. Among multiple deconvolution-based algorithms for immune infiltration, Hypoxia-score presented a general immunosuppressive efficacy across multiple datasets, as evidenced by a broad negative correlation with immune cell infiltration. By the likelihood that each group may have specific drug sensitivity to multiple chemotherapeutic and targeted agents. Results showed that high-risk scoring patients were more sensitive to Staurosporine, Sabutoclax, and AZD8055, while low-risk patients were more sensitive to Bortezomib, Dactinomycin, Docetaxel, Daporinad, Sepantronium, and bromide. In the immunotherapy cohort, the Hypoxia-score presented the ability to discriminate for immunotherapy efficacy. The distribution of Hypoxia-score in single-cell descending space was calculated using AddModuleScore and was found to be distributed across the various cell types annotated in the single-cell analysis. It is suggested that various cells in the tumour microenvironment are involved in hypoxia gene set processes to varying degrees.
CONCLUSION
The Hypoxia-score proves to be a valuable tool for assessing the prognosis of gastric cancer patients and guiding drug treatments, providing significant guidance for clinical diagnosis and treatment in the context of gastric cancer.
Topics: Humans; Prognosis; Stomach Neoplasms; Adenocarcinoma; Docetaxel; Biomarkers; Tumor Microenvironment
PubMed: 38073300
DOI: 10.1002/tox.24064 -
Journal of Immunology (Baltimore, Md. :... Sep 2022The activation of memory T cells is a very rapid and concerted cellular response that requires coordination between cellular processes in different compartments and on...
The activation of memory T cells is a very rapid and concerted cellular response that requires coordination between cellular processes in different compartments and on different time scales. In this study, we use ribosome profiling and deep RNA sequencing to define the acute mRNA translation changes in CD8 memory T cells following initial activation events. We find that initial translation enables subsequent events of human and mouse T cell activation and expansion. Briefly, early events in the activation of Ag-experienced CD8 T cells are insensitive to transcriptional blockade with actinomycin D, and instead depend on the translation of pre-existing mRNAs and are blocked by cycloheximide. Ribosome profiling identifies ∼92 mRNAs that are recruited into ribosomes following CD8 T cell stimulation. These mRNAs typically have structured GC and pyrimidine-rich 5' untranslated regions and they encode key regulators of T cell activation and proliferation such as Notch1, Ifngr1, Il2rb, and serine metabolism enzymes Psat1 and Shmt2 (serine hydroxymethyltransferase 2), as well as translation factors eEF1a1 (eukaryotic elongation factor α1) and eEF2 (eukaryotic elongation factor 2). The increased production of receptors of IL-2 and IFN-γ precedes the activation of gene expression and augments cellular signals and T cell activation. Taken together, we identify an early RNA translation program that acts in a feed-forward manner to enable the rapid and dramatic process of CD8 memory T cell expansion and activation.
Topics: 5' Untranslated Regions; Animals; CD8-Positive T-Lymphocytes; Cycloheximide; Dactinomycin; Glycine Hydroxymethyltransferase; Humans; Immunologic Memory; Interleukin-2; Lymphocyte Activation; Memory T Cells; Mice; Peptide Elongation Factor 2; Peptide Elongation Factors; Pyrimidines; RNA, Messenger; Serine
PubMed: 36002234
DOI: 10.4049/jimmunol.2100537 -
Journal of Biomolecular Structure &... 2023Natural products have emerged as major leads for the discovery and development of new anti-cancer drugs. The plant-derived anti-cancer drugs account for approximately... (Review)
Review
Natural products have emerged as major leads for the discovery and development of new anti-cancer drugs. The plant-derived anti-cancer drugs account for approximately 60% and the quest for new anti-cancer agents is in progress. Anti-cancer leads have been isolated from plants, animals, marine organisms, and microorganisms from time immemorial. The process of semisynthetic modifications of the parent lead has led to the generation of new anti-cancer agents with improved therapeutic efficacy and minimal side effects. The various chemo-informatics tools, bioinformatics, high-throughput screening, and combinatorial synthesis are able to deliver the new natural product lead molecules. Plant-derived anticancer agents in either late preclinical development or early clinical trials include taxol, vincristine, vinblastine, topotecan, irinotecan, etoposide, paclitaxel, and docetaxel. Similarly, anti-cancer agents from microbial sources include dactinomycin, bleomycin, mitomycin C, and doxorubicin. In this review, we highlighted the importance of natural products leads in the discovery and development of novel anti-cancer agents. The semisynthetic modifications of the parent lead to the new anti-cancer agent are also presented. Further, the leads in the preclinical settings with the potential to become effective anticancer agents are also reviewed.Communicated by Ramaswamy H. Sarma.
PubMed: 36255181
DOI: 10.1080/07391102.2022.2134212 -
Pediatrics Nov 2022We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment of Wilms tumor.
OBJECTIVES
We aimed to clinically characterize the health, neurocognitive, and physical function outcomes of curative treatment of Wilms tumor.
METHODS
Survivors of Wilms tumor (n = 280) participating in the St. Jude Lifetime Cohort, a retrospective study with prospective follow-up of individuals treated for childhood cancer at St. Jude Children's Research Hospital, were clinically evaluated and compared to age and sex-matched controls (n = 625). Health conditions were graded per a modified version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Standardized neurocognitive testing was graded by using age-adjusted z-scores. Impaired physical function was defined by age- and sex-matched z-scores >1.5 SD below controls. Modified Poisson regression was used to compare the prevalence of conditions and multivariable logistic regression to examine treatment associations.
RESULTS
Median age at evaluation was similar between survivors and controls (30.5 years [9.0-58.0] and 31.0 [12.0-70.0]). Therapies included nephrectomy (100%), vincristine (99.3%), dactinomycin (97.9%), doxorubicin (66.8%), and abdominal (59.3%) and/or chest radiation (25.0%). By age 40 years, survivors averaged 12.7 (95% confidence interval [CI] 11.7-13.8) grade 1-4 and 7.5 (CI: 6.7-8.2) grade 2 to 4 health conditions, compared to 4.2 (CI: 3.9-4.6) and 2.3 (CI: 2.1-2.5), respectively, among controls. Grade 2 to 4 endocrine (53.9%), cardiovascular (26.4%), pulmonary (18.2%), neurologic (8.6%), neoplastic (7.9%), and kidney (7.2%) conditions were most prevalent. Survivors exhibited neurocognitive and physical performance impairments.
CONCLUSIONS
Wilms tumor survivors experience a threefold higher burden of chronic health conditions compared to controls and late neurocognitive and physical function deficits. Individualized clinical management, counseling, and surveillance may improve long-term health maintenance.
Topics: Child; Humans; Adult; Retrospective Studies; Prospective Studies; Survivors; Wilms Tumor; Chronic Disease; Kidney Neoplasms; Outcome Assessment, Health Care
PubMed: 36300342
DOI: 10.1542/peds.2022-056918 -
Journal of Natural Products Aug 2021Through precursor-directed biosynthesis, feeding halogenated (F-, Cl-, Br-, I-) or methoxy-substituted 4-methyl-3-hydroxyanthranilic acid (4-MHA) analogues to the...
Through precursor-directed biosynthesis, feeding halogenated (F-, Cl-, Br-, I-) or methoxy-substituted 4-methyl-3-hydroxyanthranilic acid (4-MHA) analogues to the -deleted mutant strain of SCSIO ZS0073 led to the production of ten new actinomycin analogues (-). Several of the actinomycin congeners displayed impressive antimicrobial activities, with MIC values spanning 0.06-64 μg/mL to clinically derived antibiotic resistant pathogens, including , , and , with low cytotoxicity.
Topics: Anti-Infective Agents; Candida albicans; Cell Line, Tumor; Dactinomycin; Enterococcus faecium; Halogenation; Humans; Microbial Sensitivity Tests; Molecular Structure; Staphylococcus aureus; Streptomyces
PubMed: 34270246
DOI: 10.1021/acs.jnatprod.1c00294