Mechanistic modelling of targeted pulmonary delivery of dactinomycin iron oxide-loaded nanoparticles for lung cancer therapy.

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.

Dactinomycin in acute myeloid leukemia with NPM1 mutations.

OBJECTIVES: Complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug. Here, we report a single-center experience of compassionate use of dactinomycin in untreated or relapsed/ refractory NPM1-mutated AML. METHODS: From September 2015 to February 2019, 26 adult patients with NPM1-mutated AML received dactinomycin in different situations: front-line treatment in 4 unfit patients (16%); morphologic (n = 16, 62%), molecular relapses (n = 4, 16%), refractory disease (n = 1, 13%), or postremission therapy in second complete response (n = 1, 13%). RESULTS: Median age was 62.5 years. Median number of dactinomycin cycle was 1 (1-8), and 7 patients (27%) received more than 3 cycles. Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy achieved complete remission after the first cycle of dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front-line therapy. Grade 3-4 adverse events were thrombocytopenia (n = 11, 42%), neutropenia (n = 11, 42%), GI toxicity (n = 6, 23%), mucositis (n = 5, 19%), lung infection (n = 5, 19%), and skin rash (n = 2, 7.6%). CONCLUSIONS: Dactinomycin is an inexpensive and easily available drug that may induce significant responses in few AML patients with NPM1 mutations with an acceptable safety profile.

Risk factors for second-line dactinomycin failure after methotrexate treatment for low-risk gestational trophoblastic neoplasia: a retrospective study.

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.

Synergy between Photodynamic Therapy and Dactinomycin Chemotherapy in 2D and 3D Ovarian Cancer Cell Cultures.

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.

Evaluation of the therapeutic effects of rice husk nanosilica combined with platelet-derived growth factor in hepatic veno-occlusive disease.

Veno-occlusive disease is an important pattern of hepatotoxicity associated with antineoplastic drugs. The study investigated the possible therapeutic effects of RHS nanoparticles combined with a PDGF on veno-occlusive disease (VOD) in liver elicited in rats with DAC. In this work, nanosilica (SiO2) was successfully prepared from rice husk, and its physicochemical characteristics were investigated using EDX, XRD, N2 adsorption-desorption isotherm, SEM, and TEM. Forty-eight male Sprague-Dawely rats were distributed into 6 groups, with 8 rats in each. The first group served as the control. In the second group, animals were infused with DAC (0.015 mg/kg; 1-3 days) by intraperitoneal injection (i.p.). In the third group, rats were injected i.p. with DAC, and then at 24 h following the last dose of DAC, received nano-RHS incorporated with PDGF twice a week for 4 weeks. In the fourth group, normal animals were injected with RHS. In the fifth group, normal rats received PDGF, and in the sixth group, normal rats received nano-RHS combined with PDGF. The prepared nanosilica showed type II adsorption isotherm characteristic for mesoporous materials with a specific surface area of 236 m2/g. TEM imaging confirmed the production of nanoparticles via the followed preparation procedure. Radical scavenging potential for nano-RHS was determined using two different in-vitro assays: DPPH, and ABTS radicals. The results of this work show that administration of nano-RHS combined with PDGF significantly reversed the oxidative stress effects of DAC as evidenced by a decrease in liver function. It can be concluded that the nano-RHS combined with PDGF is useful in preventing oxidative stress and hepatic VOD induced by chemotherapy such as DAC.

[EMA/CO regimen for chemotherapy 24 patients with ultra high-risk gestational trophoblastic neoplasia].

Objective: To evaluate etoposide, methotrexate and dactinomycin (EMA) /cyclophosphamide and vincristine (CO) regimen for treatment of ultra high-risk gestational trophoblastic neoplasia (GTN) . Methods: A total of twenty-four ultra high-risk patients who had International Federation of Gynecology and Obstetrics (FIGO) prognostic scores greater or equal to 12 with liver, brain, or extensive metastases did poorly when treated with primary chemotherapy admitted in Women's Hospital, School of Medicine, Zhejiang University from January 2001 to December 2015. All of the patients were treated by EMA/CO regimen and followed up to death or December 2017. The clinical data of patients were analyzed retrospectively and the efficacy and toxicity of EMA/CO were evaluated. Results: All of the cases with ultra high-risk GTN had FIGO prognostic scores ≥12 (ranged 12-18, median 13.0) . Twenty patients (83%, 20/24) received EMA/CO regimen as primary treatment and 4 patients (17%, 4/24) had a history of failed chemotherapy. Seven patients (29%, 7/24) had metastasis of liver or brain and 17 patients (71%, 20/24) had no metastasis of liver and brain. Twenty-four patients received totally 167 courses of EMA/CO regimen (average 7.0 courses) . Sixteen patients achieved complete remission and 8 patients showed drug-resistant. The complete remission rate was 67% (16/24) and the resistance rate was 33% (8/24) . Of the 16 patients who got complete remission, 6 cases were treated with EMA/CO regimen alone, and 10 cases were treated by chemotherapy combined with surgery. For the 8 patients who showed drug-resistant to EMA/CO, 5 cases of them received EMA/etoposide and cisplatin (EP) regimen and 3 cases got remission, 1 case received methotrexate, dactinomycin and cyclophosphamide (MAC) regimen and got remission, 2 cases gave up treatment because of economic factors. The side effects of EMA/CO mainly included Ⅲ-Ⅳ degree neutropenia, anemia and alopecia. The incidence of Ⅲ-Ⅳ degree neutropenia during the treatment of EMA/CO was 21.6% (36/167) , the incidence of anemia was 96.4% (161/167) , and the incidence of alopecia was 60.5% (101/167) . In these 24 ultra high-risk GTN patients, 4 patients died during follow-up. In the 20 patients who got complete remission, no recurrence or secondary tumor by chemotherapy were occurred. Conclusion: EMA/CO is an effective regimen with manageable toxicity for patients with ultra high-risk GTN.

Infantile fibrosarcoma treated with postoperative vincristine and dactinomycin.

Infantile fibrosarcoma is a non-rhabdomyosarcoma soft-tissue sarcoma that occurs in infancy and which has a relatively good prognosis. A vincristine and dactinomycin (VA) regimen has been shown to be effective, although the duration of chemotherapy has not been well defined. We describe the case of a 4-month-old boy with a mass at the left dorsum of the foot who was diagnosed with infantile fibrosarcoma after resection of the tumor, the margin of which was macroscopically positive. VA treatment was carried out with careful monitoring of response and adverse effects. Pancytopenia was seen during the second cycle, and therapy was reduced thereafter. The treatment was continued for 38 weeks (12 cycles). There was no functional impairment, and no evidence of recurrence at 18 months after therapy.

Initial Diagnosis and Treatment of Low-Risk Gestational Trophoblastic Neoplasia.

Gestational trophoblastic neoplasia (GTN) is a rare form of cancer that is treated according to the World Health Organization (WHO) risk score, which predicts responsiveness to single-agent chemotherapy. Patients with WHO risk scores ≤6 have low-risk GTN, for which cure rates near 100%. Most women with low-risk GTN will respond to single-agent chemotherapy, which is given with either methotrexate or dactinomycin, and allows women to retain their fertility. This article also discusses less common treatment paradigms including second dilation and curettage and hysterectomy, as well as the emerging role of immunotherapy in managing low-risk GTN.

Resistance to single-agent chemotherapy in low-risk gestational trophoblastic neoplasia.

Background: Methotrexate (MTX) and actinomycin D (ActD) have been used as first-line chemotherapy agents in the treatment of low-risk gestational trophoblastic neoplasia (GTN). Although low-risk GTN is considered a curable disease, its reported primary remission rates of 49 to 93% reflect the difficulties of treatment and different factors influencing it. Hence, this study aimed to determine the remission rates and related factors of single-agent chemotherapy resistance in low-risk GTN patients. Methods: This retrospective study included patients with diagnosed low-risk GTN who received either MTX once a week (IM, 30mg/m2) or ActD once every two weeks (pulsed IV, 1.25mg/m2). Then, the patients were followed-up until complete remission or single-agent treatment failure to assess resistance rate and related factors. Results: Eighty-four patients were included in the study (18 patients were receiving MTX and 66 patients were receiving ActD). 85.7% of all participants achieved complete remission after first-line chemotherapy (72.2% in MTX vs 89.4% in ActD). There was a significant association for higher tumor size (P=0.046), the occurrence of metastasis (P=0.019), and pretreatment ß-HCG levels (P=0.005) with resistance to treatment. Conclusion: This study demonstrated higher tumor size, the occurrence of metastasis, and pretreatment ß-HCG levels have been associated with increased resistance to first-line chemotherapy agents.

Assessment of transcription inhibition as a characteristic of immunogenic cell death.

Anticancer drugs that suppress DNA-to-RNA transcription are particularly efficient in stimulating immunogenic cell death and hence eradicate malignant cells in a way that they will ignite an antitumor immune response. This is therapeutically relevant as it allows treatment response to last beyond drug discontinuation. For this reason, it is important to measure transcription inhibition in a precise fashion. Here, we detail two complementary assays for the assessment of transcription inhibition, one that detects the physical separation of fibrillarin and nucleolin by two-color immunofluorescence and another that measures the diminution of incorporated 5-ethynyl uridine (EU) into RNA, as revealed by click chemistry and the per-cell-intensity of a fluorescent signal.

Chemotherapy initiation with single-course methotrexate alone or combined with dactinomycin versus multi-course methotrexate for low-risk gestational trophoblastic neoplasia: a multi-centric randomized clinical trial.

We aimed to evaluate the effectiveness and safety of single-course initial regimens in patients with low-risk gestational trophoblastic neoplasia (GTN). In this trial (NCT01823315), 276 patients were analyzed. Patients were allocated to three initiated regimens: single-course methotrexate (MTX), single-course MTX + dactinomycin (ACTD), and multi-course MTX (control arm). The primary endpoint was the complete remission (CR) rate by initial drug(s). The primary CR rate was 64.4% with multi-course MTX in the control arm. For the single-course MTX arm, the CR rate was 35.8% by one course; it increased to 59.3% after subsequent multi-course MTX, with non-inferiority to the control (difference -5.1%,95% confidence interval (CI) -19.4% to 9.2%, P = 0.014). After further treatment with multi-course ACTD, the CR rate (93.3%) was similar to that of the control (95.2%, P = 0.577). For the single-course MTX + ACTD arm, the CR rate was 46.7% by one course, which increased to 89.1% after subsequent multi-course, with non-inferiority (difference 24.7%, 95% CI 12.8%-36.6%, P < 0.001) to the control. It was similar to the CR rate by MTX and further ACTD in the control arm (89.1% vs. 95.2%, P =0.135). Four patients experienced recurrence, with no death, during the 2-year follow-up. We demonstrated that chemotherapy initiation with single-course MTX may be an alternative regimen for patients with low-risk GTN.

Metastatic primary brain rhabdomyosarcoma in a pediatric patient: illustrative case.

BACKGROUND: Primary intracranial rhabdomyosarcoma is an extraordinarily rare malignant tumor, with even fewer presenting with distant metastasis. To date, only five cases, including the one presented here, have been reported to present metastatic activity. OBSERVATIONS: A 12-year-old boy presented with a few days of headache, nausea, vomiting, but no neurological deficit. Brain computed tomography and magnetic resonance imaging demonstrated hydrocephalus and a cystic lesion with left parieto-occipital extension. After resection, pathology reported primary rhabdomyosarcoma, with positive desmin and myogenin on immunohistochemistry. The patient presented with pulmonary metastasis. The patient had an overall survival of 21 months after diagnosis with optimal treatment. LESSONS: Rhabdomyosarcoma is a malignant neoplasm arising from undifferentiated skeletal muscle cells, with morphological, immunohistochemical, ultrastructural, or molecular genetic evidence of primary skeletal muscle differentiation. It presents with a rapidly worsening clinical course and the final outcome is poor. Treatment is widely based on protocols that have been proven to be effective in extracranial versions of these tumors, although repeatedly ineffective. Primary brain rhabdomyosarcoma poses a diagnostic challenge because of its infrequent presentation, grade of undifferentiation and tumor heterogeneity. Immunohistochemical and genetic testing have proven to be useful tools for diagnosis.

Potential secondary metabolite from Indonesian Actinobacteria (InaCC A758) against Mycobacterium tuberculosis.

OBJECTIVES: This study explored Indonesian Actinobacteria which were isolated from Curcuma zedoaria endophytic microbes and mangrove ecosystem for new antimycobacterial compounds. MATERIALS AND METHODS: Antimycobacterial activity test was carried out against Mycobacterium tuberculosis H37Rv. Chemical profiling of secondary metabolite using Gas Chromatography-Mass Spectroscopy (GC-MS) and High Resolution-Mass Spectroscopy (HR-MS) was done to the ethyl acetate extract of active strain InaCC A758. Molecular taxonomy analysis based on 16S rRNA gene and biosynthetic gene clusters analysis of polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) from InaCC A758 have been carried out. Bioassay guided isolation of ethyl acetate extract was done, then structural elucidation of active compound was performed using UV-Vis, FT-IR, and NMR spectroscopy methods. RESULTS: The chemical profiling using HR-MS revealed that InaCC A758 has the potential to produce new antimycobacterial compounds. The 16S rRNA gene sequencing showed that InaCC A758 has the closest homology to Streptomyces parvus strain NBRC 14599 (99.64%). In addition, InaCC A758 has NRPS gene and related to S. parvulus (92% of similarity), and also PKS gene related to PKS-type borrelidin of S. rochei and S. parvulus (74% of similarity). Two compounds with potential antimycobacterial were predicted as 1) Compound 1, similar to dimethenamid (C12H18ClNO2S; MW 275.0723), with MIC value of 100 µg/ml, and 2) Compound 2, actinomycin D (C62H86N12O16; MW 1254.6285), with MIC value of 0.78 µg/ml. CONCLUSION: Actinomycin D has been reported to have antimycobacterial activity, however the compound has been predicted to resemble dimethenamid had not been reported to have similar activity.

Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress.

Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre-mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long-term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune-dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm-selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction.

Treatment of stage I anaplastic Wilms' tumour: a report from the Children's Oncology Group AREN0321 study.

BACKGROUND: In the fifth National Wilms Tumor Study (NWTS-5), the 4-year event-free survival (EFS) and overall survival (OS) estimates for 29 patients with stage I focal (n = 10) or diffuse (n = 19) anaplastic Wilms' tumour (AWT) treated with vincristine and dactinomycin without flank radiation were 69.5% and 82.6%, respectively. The Children's Oncology Group AREN0321 study evaluated whether adding doxorubicin and flank radiation improves survival for these patients. PATIENTS AND METHODS: Tumour histology and stage were confirmed by real-time central pathology, surgery and radiology review. The patients received 25 weeks of vincristine, dactinomycin and doxorubicin (cumulative dose 150 mg/m2) with flank radiation (1080 cGy). We retrospectively analysed outcomes of all patients with stage I AWT enrolled in NWTSs 1-5 and AREN0321 with respect to treatment regimens. RESULTS: Eighteen patients with stage I AWT (8 focal and 10 diffuse) were enrolled on AREN0321. With a median follow-up of 4.6 years, the 4-year EFS and OS were 100%. One patient with diffuse AWT had pulmonary relapse 4.12 years after diagnosis. In the 112 patients with stage I AWT treated in NWTSs 1-5 and AREN0321, the EFS was significantly improved with doxorubicin treatment (p = 0.01; 4-year EFS: 97.2% [95% confidence interval {CI}: 91.3-100] vs. 77.5% [95% CI: 67.6-87.4]) but not by flank radiation (p = 0.15). CONCLUSIONS: Treatment of stage I AWT with vincristine, dactinomycin, doxorubicin and flank radiation in AREN0321 yielded excellent survival outcomes. Retrospective analysis of AREN0321 and NWTS patients suggests that doxorubicin had a greater contribution to the excellent outcomes than radiation.

Comparing and evaluating the efficacy of methotrexate and actinomycin D as first-line single chemotherapy agents in low risk gestational trophoblastic disease.

OBJECTIVE: The aim of this study was to compare responses to single-agent chemotherapies and evaluate the predictive factors of resistance in low risk (LR) gestational trophoblastic disease (GTD). The chemotherapy agents included methotrexate (MTX) and actinomycin D (ACT-D). METHODS: We conducted a retrospective study of 126 patients with GTD who were treated between 2000 and 2013. A total of 71 patients with LR GTD were treated with MTX (8-day regimen or weekly regimen, n=53) or ACT-D (bi-weekly pulsed regimen or 5-day regimen, n=18). The successful treatment group and the failed treatment group were compared and analyzed to identify prognostic factors. RESULTS: The complete response rates were 83.3% for ACT-D and 62.2% for MTX, with no statistically significant difference. There was no severe adverse effect reported for either group. Longer interval durations from the index pregnancy (>2 months, p=0.040) and larger tumor size (>3 cm, p=0.020) were more common in non-responders than in responders; these results were statistically significant. CONCLUSION: Based on our results, ACT-D may be a better option than MTX as a first-line single chemotherapy agent for LR GTD. The bi-weekly pulsed ACT-D regimen had minimal, or at least the same, toxicities compared with MTX. However, due to the lack of strong supporting evidence, it cannot be conclusively stated that this is the best single agent for first-line chemotherapy in LR GTD patients. Further larger controlled trials will be necessary to establish the best guidelines for GTD treatment.

The surgical management of paediatric bladder and prostate rhabdomyosarcoma.

BACKGROUND: The surgical management of paediatric bladder/prostate rhabdomyosarcoma (B/P RMS) continues to develop, with the goal of maximising organ preservation while achieving successful cancer control. The timing of radiotherapy and surgical excision to improve event-free survival (EFS) and overall survival (OS) remains controversial. METHODS: Previous reports in English on B/P RMS over the past 15 years were identified and reviewed, focusing on studies comparing the effects of radiotherapy and surgery for local control, the effect of local control on OS, and improved means of diagnosing viable tumour after chemotherapy. RESULTS: The concept of lowering the 'cost of cure' drives current protocols. Bladder-sparing surgery is possible for 80% of patients after initial chemotherapy, with a mean 5-year OS of 85%. Overall, half of the patients are continent of urine, and adding radiotherapy might increase the risk of incontinence. Previous studies suggesting that early radiotherapy achieved better EFS than delayed radiotherapy did not control for stage and size of the tumour, which are the primary determinants of EFS. Improved local control does not automatically translate into improved OS. CONCLUSIONS: The current role for the surgical management in B/P RMS is to achieve local control of tumours that do not respond to chemotherapy and radiotherapy. An improved means of detecting viable tumour after initial chemotherapy would improve the ability to decide when local therapy is necessary. The continuing challenge for urologists managing these children is knowing when bladder-sparing surgery would be the best therapy.

Dactinomycin-induced Hepatic Sinusoidal Obstruction Syndrome Responding to Treatment with N-acetylcysteine.

Hepatic sinusoidal obstruction syndrome is commonly described in pediatric oncology as a complication of chemotherapy. It has also been occasionally reported in adult cancer patients. Treatment is largely supportive with fluid restriction. A 16-month-old girl with stage II Wilms tumor receiving post-nephrectomy chemotherapy with dactinomycin and vincristine developed hepatic sinusoidal obstruction syndrome with painful hepatomegaly, ascites with significant weight gain, grossly deranged liver function, severe thrombocytopenia, and reversal of blood flow in the portal vein on Doppler sonography. Treatment with N-acetylcysteine was followed by complete resolution of clinical signs and amelioration of laboratory abnormalities within 72 hours of treatment. N-acetylcysteine is a safe and probably an effective treatment for dactinomycin-induced hepatic sinusoidal obstructive syndrome.

Treatment of low-risk gestational trophoblastic neoplasia comparing biweekly eight-day Methotrexate with folinic acid versus bolus-dose Actinomycin-D, among Brazilian women / Tratamento da neoplasia trofoblástica gestacional de baixo-risco, comparando aplicação quinzenal de oito dias de Metotrexato com ácido folínico versus Actinomicina D em bolo, em mulheres brasileiras

PURPOSE: To compare two single-agent chemotherapy (ChT) regimens evaluating, in first-line treatment, response and side effects and, in final single-agent treatment, the outcomes, among Brazilian patients with low-risk gestational trophoblastic neoplasia (GTN), according to International Federation of Gynecology and Obstetrics (FIGO) 2002. METHODS: Retrospective analysis of two concurrent cohorts with 194 low-risk GTN patients: from 1992 to 2012, as first-line treatment, 115 patients received 4 intramuscular doses of methotrexate alternated with 4 oral doses of folinic acid (MTX/FA) repetead every 14 days and, since 1996, 79 patients received an endovenous bolus-dose of actinomycin D (Act-D), biweekly. At GTN diagnosis, patient opinion was taken into consideration when defining the initial single-agent ChT regimen, and when there was resistance or toxicity to one regimen, the other drug was used preferentially. This study was approved by the Irmandade da Santa Casa de Misericórdia de Porto Alegre Ethical Committee. RESULTS: Both groups were clinically similar (p>0.05). In first-line treatments, frequency of complete response was similar (75.7% with MTX/FA and 67.1% with bolus Act-D); the number of ChT courses -median 3 (range: 1-10) with MTX/FA and 2 (range: 1-6) with bolus Act-D - and the time to remission -median 9 weeks (range: 2-16) with MTX/FA and 10 weeks (range: 2-16) with bolus Act-D) - were not different between the groups. In both groups, first-line side effects frequency were high but intensity was low; stomatitis was higher with MTX/FA (p<0.01) and nausea and vomit with Act-D (p<0.01). Final single-agent ChT responses were high in both groups (94.8% with MTX/FA and 83.5% with bolus Act-D; p<0.01) and 13% higher in the group initially treated with MTX/FA. Rates of hysterectomy and of GTN recurrence were low and similar. No patient died due to GTN. CONCLUSION: The two regimens had similar first-line ChT response. ...

OBJETIVO: Em mulheres brasileiras com neoplasia trofoblástica gestacional (NTG) de baixo-risco, de acordo com a Federação Internacional de Ginecologia e Obstetrícia (FIGO) 2002, comparar dois regimes de quimioterapia (Qt) por agente único avaliando resposta e efeitos colaterais no tratamento de primeira linha, e a eficácia no tratamento final por agente único de Qt. MÉTODOS: Análise retrospectiva de duas coortes concorrentes com 194 pacientes com NTG de baixo risco: de 1992 a 2012; como primeira linha, 115 pacientes receberam 4 doses intramusculares de metotrexato alternado com 4 doses orais de ácido folínico (MTX/FA) repetidos a cada 14 dias e, desde 1996, 79 pacientes receberam quinzenalmente dose em bolo de actinomicina D (Act-D) por via endovenosa. No momento do diagnóstico da NTG, a opinião da paciente foi levada em consideração para definir o regime de Qt por agente único inicial e, quando havia resistência ou toxicidade a um regime, o outro fármaco era usado preferentemente. Este estudo foi aprovado pelo Comitê de Ética da Irmandade da Santa Casa de Misericórdia de Porto Alegre. RESULTADOS: Ambos os grupos eram clinicamente semelhantes (p>0,05). Nos tratamentos de primeira linha, a frequência de resposta completa foi semelhante (75,7% com MTX/FA e 67,1% com Act-D em bolo); não houve diferença entre os grupos quanto ao número de séries de Qt - mediana 3 (intervalo: 1-10) com MTX/FA e 2 (intervalo: 1-6) com Act-D em bolo - e ao tempo para remissão - mediana 9 semanas (intervalo: 2-16) com MTX/FA e 10 semanas (intervalo: 2-16) com Act-D em bolo. Em ambos os grupos, foi elevada a frequência de efeitos colaterais no tratamento de primeira linha, mas com intensidade baixa; estomatite foi mais frequente com MTX/FA (p<0.01) e náuseas e vômitos com Act-D (p<0.01). A resposta final à Qt por agente único foi alta nos dois grupos (94,8% com MTX/FA e 83,5% com Act-D em bolo; p<0,01) e 13% maior no grupo inicialmente tratado com ...

[Effects of two inhibitors of RNA synthesis (Actinomycin D and α-amanitin) on embryonic development of an insect: Gene activity from the beginning of embryogenesis inLeptinotarsa decemlineata]. / Comparaison des effets de deux inhibiteurs de la synthèse d'ARN (Actinomycine D et α-amanitine) sur le développement embryonnaire d'un insecte: déterminisme génique du début de l'embryogénèse deLeptinotarsa decemlineata (Coleoptera).

Actinomycin D and α-amanitin were injected into the embryos ofLeptinotarsa from intravitelline cleavage stages to gastrula stages. The effect of injection was controlled. Following the treatment, embryogenesis was blocked at different stages: blastula (pseudo-blastula), abnormal gastrula and atypical germ band. The stages reached depend on the age of treatment. Treatment of intravitelline cleavage stages strongly inhibits morphogenesis: embryos are blocked mainly at the blastula stage (79 to 97%). Treatment of blastoderm formation stages shows different features: gastrulation is at first prevented in 80% of cases, but the capacity to gastrulate is acquired rapidly during the first blastodermic cell cycle; embryos treated at late blastoderm stages reach the germ band stage.From these results, two periods have been characterized in the early embryogenesis ofLeptinotarsa: 1. the intravitelline cleavage period is unaffected by the inhibitor of RNA synthesis. All information needed for cleavage and early blastoderm formation is already present in the fertilized egg, probably in the form of materialmRNA. 2. The blastoderm formation period is involved in further morphogenesis. New information, for the development of late blastula, gastrula and germ band is produced during succesive blastoderm cell cycles. The actinomycin D and α-amanitin treatments show that the acquisition of new morphogenetic capacities is contemporaneous with the arrival of nuclei in the periplasm.