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Lancet (London, England) Oct 2022Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies.
METHODS
EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667.
FINDINGS
Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%]).
INTERPRETATION
Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma.
FUNDING
The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK.
Topics: Humans; Sarcoma, Ewing; Ifosfamide; Etoposide; Vincristine; Dactinomycin; Busulfan; Melphalan; Bayes Theorem; Bone Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Disease-Free Survival
PubMed: 36522207
DOI: 10.1016/S0140-6736(22)01790-1 -
Gynecologic Oncology Feb 2023Single-agent methotrexate (MTX) is commonly used as first-line treatment for low-risk gestational trophoblastic neoplasia (LR-GTN), although no international consensus...
BACKGROUND
Single-agent methotrexate (MTX) is commonly used as first-line treatment for low-risk gestational trophoblastic neoplasia (LR-GTN), although no international consensus exists on the optimal treatment regimen to maximise complete hCG response (CR) and minimise relapse rates. Current regimens differ in the route of administration, dose scheduling, and use of flat-dose, body surface area (BSA)- or weight-based dosing. In the UK a methotrexate-folinic acid (MTX-FA) 8-day 50 mg intramuscular flat-dose regimen is used, with 15 mg oral folinic acid rescue. In LR-GTN patients, we aim to determine the effect of MTX dose adjustment by BSA and weight upon chemotherapy response and disease relapse.
METHODS
Between January 1973 and August 2020, 935 LR-GTN patients treated with first-line MTX-FA were identified from a single UK specialist trophoblastic centre. Of these, 364 were included, of which 178 (49%) had a CR to first-line MTX-FA. Subgroup analyses were performed upon: (i) patients who changed chemotherapy due to MTX toxicity (n = 33); and (ii) patients with a FIGO score of 5-6 (n = 85). Logistic regression analysis explored the relationship between BSA or weight adjusted MTX dosing and: (i) CR to first-line chemotherapy; (ii) incidence of disease relapse. Linear regression analyses assessed the correlation of BSA and weight with the number of MTX-FA cycles required to achieve CR.
RESULTS
In LR-GTN patients, BSA and weight adjusted MTX-FA dosing did not influence CR to first-line chemotherapy or the incidence of disease relapse. The number of MTX cycles required to achieve CR was not associated with BSA or weight. These findings were maintained in a subgroup analysis of FIGO 5-6 patients. The incidence of MTX toxicity was not influenced by BSA or weight.
CONCLUSIONS
In the treatment of LR-GTN, dose individualisation using BSA or weight is not required, and fixed dosing continues to be preferred as the UK standard.
Topics: Pregnancy; Female; Humans; Methotrexate; Leucovorin; Body Surface Area; Retrospective Studies; Neoplasm Recurrence, Local; Gestational Trophoblastic Disease; Drug-Related Side Effects and Adverse Reactions; Dactinomycin
PubMed: 36495594
DOI: 10.1016/j.ygyno.2022.11.025 -
Medicine Nov 20225-Fluorouracil (5-FU) and actinomycin D (ActD) are often used in chemotherapy for various cancers. Side effects are more common in bone marrow suppression, liver... (Review)
Review
RATIONALE
5-Fluorouracil (5-FU) and actinomycin D (ActD) are often used in chemotherapy for various cancers. Side effects are more common in bone marrow suppression, liver function impairment, and gastrointestinal responses. Skin effects are rare and easy to be ignored by doctors and patients, which can lead to life-threatening consequence.
PATIENT CONCERNS
We reported a 45-year-old woman patient developed skin erythema and fingernail belt in chemotherapy of 5-FU and ActD.
DIAGNOSIS
Erythema multiforme drug eruption.
INTERVENTIONS
Laboratory tests including blood and urine routine, liver and kidney function, electrolytes and coagulation function and close observation.
OUTCOMES
The rash was gone and the nail change returned.
LESSONS
Delays in diagnosis or treatment may lead to serious consequence. We should pay attention to the dosage of 5-FU and ActD, monitor adverse reactions strictly, to reduce occurrence of skin malignant events.
Topics: Female; Pregnancy; Humans; Middle Aged; Dactinomycin; Hydatidiform Mole, Invasive; Fluorouracil; Erythema Multiforme; Drug Eruptions; Uterine Neoplasms
PubMed: 36451432
DOI: 10.1097/MD.0000000000031678 -
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 -
Biochemical and Biophysical Research... Dec 2022Actinomycin D (ActD) is an antineoplastic antibiotic that has been commonly used for the treatment of various tumors, including Wilms' tumor, rhabdomyosarcoma, and...
Actinomycin D (ActD) is an antineoplastic antibiotic that has been commonly used for the treatment of various tumors, including Wilms' tumor, rhabdomyosarcoma, and gestational trophoblastic neoplasia. Recent studies have proposed actinomycin D (ActD) as a novel therapeutic candidate for glioblastoma. ActD significantly reduces tumor growth in recurrent glioblastoma patient-derived mouse models and increases survival by downregulating SOX2 expression. However, ActD treatment of brain tumors can lead to unnecessary exposure of surrounding neurons and normal glial cells to ActD. Cellular and molecular studies are required to estimate and minimize the neurological side effects of ActD. This study investigated the short- and long-term toxicological responses of the primary cortical neurons to ActD. We examined concentration-dependent survival of primary cortical neurons and differential susceptibilities of excitatory, inhibitory neurons, and glial cells to ActD. Distinct alterations in intracellular signaling pathways in cortical neurons were also studied when exposed to ActD. Importantly, we found that primary cortical neurons after ActD discontinuation showed active intracellular signaling pathways responding to extracellular neurotropic factors, but they had extremely poor transcription activity reversibility that was inhibited even by 30-min low-dose ActD exposure. These findings indicate the direct toxicity and extremely poor reversibility of ActD in neurons during chemotherapy for brain tumors.
Topics: Mice; Animals; Dactinomycin; Glioblastoma; Neoplasm Recurrence, Local; Neurons; Brain Neoplasms
PubMed: 36332475
DOI: 10.1016/j.bbrc.2022.10.083 -
Pediatric Blood & Cancer Jan 2023Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. High-risk and metastatic disease continues to be associated with very poor prognosis. RMS...
Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. High-risk and metastatic disease continues to be associated with very poor prognosis. RMS model systems that faithfully recapitulate the human disease and provide rapid, cost-efficient estimates of antitumor efficacy of candidate drugs are needed to facilitate drug development and personalized medicine approaches. Here, we present a new zebrafish-based xenotransplant model allowing for rapid and easily accessible drug screening using low numbers of viable tumor cells and relatively small amounts of water-soluble chemicals. Under optimized temperature conditions, embryonal RMS xenografts were established in zebrafish embryos at 3 h postfertilization (hpf). In proof-of-principle experiments, chemotherapy drugs with established clinical anti-RMS efficacy (vincristine, dactinomycin) and the mitogen-activated protein kinase kinase inhibitor trametinib were shown to significantly reduce the cross-sectional area of the tumors by 120 hpf. RMS xenograft models in zebrafish embryos henceforth could serve as a valuable addition to cell culture and mammalian models of RMS and represent a rapid and cost-effective solution for preclinical candidate drug testing.
Topics: Child; Animals; Humans; Zebrafish; Heterografts; Xenograft Model Antitumor Assays; Rhabdomyosarcoma, Embryonal; Rhabdomyosarcoma; Mammals
PubMed: 36317680
DOI: 10.1002/pbc.30053 -
BMC Pediatrics Oct 2022Idiopathic connective tissue disease juvenile dermatomyositis (JDM) is characterised by inflammatory myositis and distinctive skin abnormalities. Only a few cases of...
BACKGROUND
Idiopathic connective tissue disease juvenile dermatomyositis (JDM) is characterised by inflammatory myositis and distinctive skin abnormalities. Only a few cases of Dermatomyositis (DM) owing to chemotherapy used to treat cancer have been reported, despite the fact that the link between DM and cancer in adults is widely known. We describe the case of a female, age 14, who experienced DM as a side effect of chemotherapy following enucleation for retinoblastoma. We also discussed our patient's likely pathophysiology of JDM after treatment.
CASE PRESENTATION
A 14-year-old female came to our facility complaining of trouble walking and bluish-black discoloration on her neck, elbows, forehead, and knees that had been present for eight months. The patient had undergone enucleation of the left eye due to retinoblastoma, followed by 40 cycles of radiation therapy and 13 cycles of chemotherapy with Cyclophosphamide, Etoposide, Carboplatin, Vincristine, and Dactinomycin. Her serum LDH and CPK levels were high, and she tested positive for ANA. The muscle biopsy was consistent with the changes of DM. When electromyography was performed, it revealed tiny, fibrillating, polyphasic motor unit potentials and sharp, positive waves that were suggestive with DM. A diagnosis of JDM was made after taking into account the symptoms, biochemical data, muscle biopsy, and electromyography results. The patient's symptoms started to get better once methotrexate and oral corticosteroids were started.
CONCLUSION
This case report emphasises the value of ongoing observation after cancer chemotherapy because specific cutaneous and muscle symptoms may lead paediatricians to consider the possibility of chemotherapy-induced JDM, which is uncommon in young patients.
Topics: Adult; Humans; Female; Adolescent; Dermatomyositis; Retinoblastoma; Electromyography; Retinal Neoplasms; Antineoplastic Agents
PubMed: 36316673
DOI: 10.1186/s12887-022-03704-5 -
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 -
Disease Markers 2022Macrophages are heterogeneous cells that can be polarized into M1 or M2 phenotype. mA "reader" YTH domain family protein 2 (YTHDF2) has been the mA binding protein with...
Macrophages are heterogeneous cells that can be polarized into M1 or M2 phenotype. mA "reader" YTH domain family protein 2 (YTHDF2) has been the mA binding protein with the highest activity, which can recognize and disturb mA-containing mRNA in processing bodies to reduce mRNA stability. YTHDF2 is recently identified as an effective RNA binding protein that modulates inflammatory gene levels within inflammatory responses. However, the role of YTHDF2 in M1/M2 macrophage polarization has not been reported. We established a M1/M2 macrophage polarization model using bone-marrow-derived macrophages and found that the expression levels of YTHDF2 in M1/M2 macrophages were both elevated. YTHDF2-knockdown macrophage polarization model was then established, and through qPCR, ELISA, and FACS, we discovered that suppressing YTHDF2 encouraged M1 polarization but restrained M2 polarization. In M1 macrophages, YTHDF2 silencing had no significant effect on p53 expression; however, in YTHDF2 knockdown, M2 macrophage p53 expression was remarkably upregulated. p53 inhibitor PFT- was then applied and revealed that suppressing p53 simultaneously promoted YTHDF2-silenced M1 polarization and facilitated M2 macrophage polarization. Actinomycin D assays were further utilized to examine the mRNA degradation level of different cytokines, and p53 mRNA degradation in YTHDF2-depleted M2 cells was discovered impeded. Western Blot analysis also implied that a deficit in YTHDF2 expression may activate MAPK and NF-B pathways. In this study, YTHDF2 induces M2 macrophage polarization by promoting the degradation of p53 mRNA. YTHDF2 suppresses M1 macrophage polarization by inhibiting NF-B, p38, and JNK signaling pathways, yet p53 remains unaffected in YTHDF2-silenced M1 macrophages.
Topics: NF-kappa B; Tumor Suppressor Protein p53; Dactinomycin; Signal Transduction; Macrophages; Cytokines; RNA-Binding Proteins; RNA, Messenger
PubMed: 36277978
DOI: 10.1155/2022/3153362 -
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