UNASSIGNED: Treatment of Ewing sarcoma (ES) requires multidisciplinary approach and deficiencies in treatment adversely affect the results. This study included patients diagnosed with ES and aimed to determine the factors affecting prognosis and investigate the efficacy of replacing actinomycin-D with carboplatin in consolidation treatment.
UNASSIGNED: Eighty-two pediatric ES patients diagnosed at a single institution between 2005 and 2020 were retrospectively evaluated. Clinical and epidemiological features, treatment modalities, prognostic criteria, and overall survival (OS) rates of patients revieved. In consolidation treatment, 22 patients were treated with actinomycin-D and 32 patients with carboplatin (500 mg/m2/dose), 24 patients could not receive consolidation treatment. The 5- and 10-year OS rates of the patients were compared.
UNASSIGNED: The 5- and 10-year OS rates of the 82 patients with ES were 46% and 40%, respectively. The 5-year OS rates in the group with localized disease (n = 55) and metastasis (n = 27) at diagnosis were 54% and 26%, respectively (p = 0.006). When evaluated according to the consolidation treatment administered both the 5- and 10-year OS rates of the patients receiving actinomycin-D were 50%. The 5-year OS rate was 58% in the carboplatin group, and the 5- and 10-year OS rates of patients that did not receive consolidation treatment was 20%.
UNASSIGNED: Survival was significantly worse in the group that did not receive consolidation treatment. Furthermore, our results suggested that carboplatin could be used effectively as an alternative to actinomycin-D in ES consolidation treatment.

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.

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/m2 (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/m2 (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.

Low-risk gestational trophoblastic neoplasia (GTN), defined as FIGO/WHO score 0-6, is highly curable with an overall survival rate, which is approximately 100%. For most low-risk GTN patients, first-line single-agent chemotherapy with either methotrexate or actinomycin-D is recommended with overall complete human chorionic gonadotrophin (hCG) response rates of 60%-90% in mostly retrospective, non-randomised studies. The few randomised trials that exist are not appropriately powered or designed to define the optimal first-line treatment. Approximately 25%-30% of low-risk patients will develop resistance to initial single-agent chemotherapy with an increase in the FIGO score, a diagnosis of choriocarcinoma, higher pre-treatment hCG and the presence of metastatic disease being associated with an increase in the risk of resistance. The optimal treatment of patients scoring WHO 5 and 6 remains poorly defined given that approximately 70%-80% of these patients develop resistance to first-line single-agent chemotherapy, and there is an urgent need to refine the FIGO/WHO scoring system so that these patients can be identified for more intensive therapy from the outset. Despite this, almost all low-risk patients who experience treatment failure with first-line monotherapy will be cured with either sequential single-agent chemotherapy or multiagent chemotherapy with or without surgery. Given the associated increased short and longer-term toxicities associated with multi-agent chemotherapy, promising strategies to reduce the exposure of women to combination chemotherapy in low-risk disease have been investigated, including the use of carboplatin and immune check-point inhibitors. Further evaluation is required to define optimal patient selection, particularly with the use of immunotherapeutic agents given their significant increased costs and lack of longer-term safety data. Although there is a clear need to revise the FIGO/WHO (2000) scoring system, consistent international use of this is recommended to facilitate the comparison of data along with future focus in the development of international collaborative translational and clinical research, including randomised controlled trials.

Actinomycin-D (Act-D) is a highly effective chemotherapeutic agent that induces apoptosis in systemic tissues. Act-D combined with other chemotherapeutic agents exhibits ototoxic effects and causes hearing impairment. To investigate the potential toxic effects of Act-D in the inner ear, we treated cochlear organotypic cultures with varying concentrations of Act-D for different durations. For the first time, we found that Act-D specifically induced HC loss and apoptosis in a dose- and time-dependent manner but not neuronal degeneration. Co-treatment with benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-FMK), a pan cysteine protease inhibitor, significantly reduced HC loss and apoptosis induced by Act-D, indicating increased cell survival. Taken together, Act-D exposure has ototoxic effects on the auditory system, while z-VAD-FMK prevents Act-D-induced hair cell damage.

Methotrexate and actinomycin-D are both effective first-line drugs for low-risk (WHO score 0-6) Gestational Trophoblastic Neoplasia (GTN) with considerable debate about which is more effective, less toxic, and better tolerated. The primary trial objective was to test if treatment with multi-day methotrexate (MTX) was inferior to pulse actinomycin-D (ACT-D). Secondary objectives included evaluation of severity and frequency of adverse events, and impact on quality of life (QOL).
This was a prospective international cooperative group randomized phase III two arm non-inferiority study (Clinical Trials Identifier: (NCT01535053). The control arm was ACT-D; the experimental arm was multi-day MTX regimen (institutional preference of 5 or 8 day). Outcome measures included complete response rate, recurrence rate, toxicity, and QOL as measured by FACT-G and FACIT supplemental items.
The complete response rates for multi-day methotrexate and pulse actinomycin-D were 88% (23/26 patients) and 79% (22/28 patients) (p = NS) respectively, there were two recurrences in each arm, and 100% of patients survived. Significant toxicity was minimal, but mouth sores (mucositis), and eye pain were significantly more common in the MTX arm (p = 0.001 and 0.01 respectively). Quality of life showed no significant difference in overall quality of life, body image, sexual function, or treatment related side effects. The study was closed for low accrual rate (target 384, actual accrual 57), precluding statistical analysis of the primary objective.
The complete response rate for multi-day methotrexate was higher than actinomycin-D, but did not reach statistical significance. The multi-day MTX regimens were associated with significantly more mucositis and were significantly less convenient.

Low-risk non-metastatic gestational trophoblastic neoplasia (GTN) has been treated with single agent chemotherapy, but second curettage is emerging as an alternative strategy with reported cure rates of 40%. We sought to estimate the cost-effectiveness of second curettage as the first line treatment of low-risk GTN.
A decision-analytic model was created using TreeAge software to compare costs and outcomes for women with WHO staged low-risk GTN undergoing treatment with 5-day methotrexate (MTX), biweekly pulsed actinomycin-D, or second curettage. Probabilities were derived from the literature. Outcomes of interest included side effects from chemotherapy, need for additional agents, hemorrhage, uterine perforation, and cure rates. Utilities were applied to discounted life expectancy at a rate of 3% to generate quality adjusted life years (QALYs). Sensitivity analyses were then performed in order to assess the robustness of our assumptions.
Of the three treatment arms, MTX was associated with the lowest cost and had similar QALYs to the other studied modalities. Second curettage was associated with 49 additional cures when applied to a theoretic cohort of 1000 women, as well as an additional 83 hemorrhages and 17 uterine perforations. Sensitivity analysis on the cure rate of second curettage revealed that second curettage was not cost-effective over MTX unless its probability of cure was 98%.
Our study found 5-day MTX was the cost-effective strategy for treatment of women with low-risk, non-metastatic GTN when compared to second curettage and actinomycin-D. In a carefully selected patient population, second curettage may be an additional treatment strategy.

Isolated limb infusion (ILI) with cytotoxic agents is a simple and effective treatment option for patients with melanoma in-transit metastases (ITMs) confined to an extremity. Data for ILIs performed in Europe are sparse and to date no Eastern European ILI experience has been reported. The aim of the current study was to evaluate the efficacy of ILI in Estonia.
Data for twenty-one patients were collected and analysed. All patients had melanoma ITMs and underwent an ILI between January 2012 and May 2018. The cytotoxic drug combination of melphalan and actinomycin-D was used. Drug circulation times were 20-30 min under mildly hyperthermic conditions (38-39 °C). Primary outcome measures were treatment response and overall survival.
Nineteen lower limb and two upper limb ILIs were performed. The female to male ratio was 18:3. The overall response rate (complete + partial response) was 76% (n = 16), with a complete response in 38% (n = 8). The overall long-term limb salvage rate was 90% (n = 19). During follow-up, eight patients (38%) died, two due to metastatic melanoma. Five-year overall survival was 57%.
This first Eastern European report of ILI for melanoma ITMs shows results comparable to those from other parts of the world. In this era of effective targeted and immune therapies, ILI remains a useful treatment option, with a high overall response rate and durable responses in patients with melanoma ITMs confined to a limb.

Ectopic pregnancy is an urgent clinical condition that represents a serious hazard to reproductive power, and thus threatens woman\'s health. Commonly, methotrexate is considered for early resolution of placental tissue. Despite its potential advantages such as minimizing hospitalization and quick recovery, its high skin and gastrointestinal side-effects and requiring time monitoring may limit its application. Recently, high effectiveness of the single-agent chemotherapy agents, such as Actinomycin D, has been suggested. Herein, a case of methotrexate-resistant EP that was successfully treated with Actinomycin D was described.

To evaluate the impact of periodic shortage of actinomycin-d (Act-d) in the treatment of Brazilian patients with low-risk gestational trophoblastic neoplasia (GTN) after methotrexate and folinic acid rescue (MTX/FA) resistance, treated alternately with carboplatin or etoposide as a second-line regimen.
Retrospective cohort that included patients with failure of first-line MTX/FA regimen for low-risk GTN treated at Rio de Janeiro Federal University, Universidade Federal de São Paulo and Irmandade da Santa Casa de Misericórdia de Porto Alegre, from January/2010- December/2017.
From 356 patients with low-risk GTN treated with MTX/FA, 75 (21.1%) developed resistance, of which 40 (53.3%) received Act-d, 23 (30.7%) carboplatin and 7 (9.3%) etoposide. Although patients treated with single-agent chemotherapy as a second-line regimen had comparable clinical and primary treatment characteristics, those treated with Act-d (80%, p = 0.033) or etoposide (71.4%, p = 0.025) had higher remission rates when compared with carboplatin (47.8%). Only 29% of patients treated with carboplatin received the chemotherapy cycles without delay compared to Act-d (98%, p < 0.001) or etoposide (85%, p = 0.009). Patients treated with carboplatin had significantly more hematological toxicity, notably anemia (30.4%, p = 0.008), lymphopenia (47.7%, p < 0.001) and thrombocytopenia (43.4%, p < 0.001), as well as a higher occurrence of febrile neutropenia (14.4%, p = 0.044) and vomiting (60%, p < 0.001) than those receiving Act-d (5%, none, 2.5%, none, 10%, respectively).
Carboplatin did not have a satisfactory clinical response rate, likely due to severe hematological toxicity, which postponed chemotherapy. Our results reinforce the preference for Act-d as a second-line agent in patients with low-risk GTN after MTX/FA resistance.