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Research on the relationships between oligoelements (OE) and the development of cancer or its prevention is a field that is gaining increasing relevance. The aim was to evaluate OE and their interactions with oncology treatments (cytarabine or etoposide) to determine the effects of this combination on biogenic amines and oxidative stress biomarkers in the brain regions of young Wistar rats. Dopamine (DA), 5-Hydroxyindoleacetic acid (5-Hiaa), Glutathione (Gsh), Tiobarbituric acid reactive substances (TBARS) and Ca+2, Mg+2 ATPase enzyme activity were measured in brain regions tissues using spectrophometric and fluorometric methods previously validated. The combination of oligoelements and cytarabine increased dopamine in the striatum but decreased it in cerebellum/medulla-oblongata, whereas the combination of oligoelements and etoposide reduced lipid peroxidation. These results suggest that supplementation with oligoelements modifies the effects of cytarabine and etoposide by redox pathways, and may become promising therapeutic targets in patients with cancer. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation (ASCT) is a salvage therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). We have developed a novel conditioning regimen called CEAC (oral semustine 250 mg/m2 d-6, etoposide 300 mg/m2 d-5 ~ d-2, cytarabine 500 mg/m2 d-5 ~ d-2, and cyclophosphamide 1200 mg/m2 d-5 ~ d-2) In lymphoma patients in China. Here, we conducted a study to compare the conventional BEAM regimen with the CEAC regimen in 110 DLBCL patients. Propensity-score matching was performed in a 1:4 ratio (22 patients received BEAM and 88 received CEAC). Our results showed no significant difference in the overall response rate (95% vs 97%, P = 1.000) and complete response rate (66% vs 73%, P = 0.580) between the two cohorts. The 5-year progression-free survival (PFS), 5-year overall survival (OS), and 5-year cumulative incidence of relapse (CIR) for all patients were 72% (95% CI 62%–82%), 92% (95% CI 86%–97%), and 29% (95% CI 17%–38%), respectively. There was no significant difference in the 5-year PFS (80% vs 70%, P = 0.637), 5-year OS (95% vs 91%, P = 0.496), and 5-year CIR (20% vs 30%, P = 0.733) between cohorts. In terms of safety, the CEAC cohort had a lower incidence rate of grade 1–2 gastrointestinal hemorrhage (P = 0.023) and severe nausea (P = 0.007) compared with the BEAM cohort. In conclusion, the CEAC regimen seems to be a suitable alternative to the BEAM regimen for ASCT in DLBCL patients. [ABSTRACT FROM AUTHOR]

Impaired spermatogenesis and male infertility are common consequences of chemotherapy drugs used in patients with testicular cancer. The present study investigated the effects of sodium alginate (NaAL) on testicular toxicity caused by bleomycin, etoposide, and cisplatin (BEP). Rats in group 1 received normal saline, while groups 2 and 3 were treated with 25 and 50 mg/kg of NaAL, respectively. Group 4 was treated with a 21-day cycle of BEP (0.5 mg/kg bleomycin, 5 mg/kg etoposide, and 1 mg/kg cisplatin), and groups 5 and 6 received BEP regimen plus 25 and 50 mg/kg of NaAL, respectively. Then, sperm parameters, testosterone levels, testicular histopathology and stereological parameters, testicular levels of malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC), and the expression of apoptosis-associated genes including Bcl2, Bax, Caspase3, p53, and TNF-α were evaluated. Our findings revealed that NaAL improved sperm parameters, testosterone levels, histopathology, and stereology parameters in BEP-administrated rats. NaAL also improved testis antioxidant status by enhancing TAC and ameliorating MDA and NO. Further, modifications to the expression of Bcl2, Bax, Caspase3, p53, and TNF-α suggested that NaAL alleviated BEP-induced apoptosis and inflammation. Collectively, NaAL protects rats' testes against BEP-evoked toxicity damage through the modulation of nitro-oxidative stress, apoptosis, and inflammation. [ABSTRACT FROM AUTHOR]

Emerging pollutants are compounds arising from human development, such as personal care products and pharmaceutical drugs, that reach rivers, lakes, and groundwater through wastewaters and have a potential risk to human health and the environment, which are not yet addressed in any laws. Anticancer drugs are a class of pharmaceutical drugs that exhibit recalcitrant behavior to conventional wastewater treatments. They have been found in domestic, industrial, and hospital wastewater, and some studies proved they can be mutagenic, genotoxic, and teratogenic to humans and wildlife. On this subject, the present study describes the enzymatic degradation of etoposide by several laccase activities and pHs. Moreover, the kinetic studies were performed in etoposide concentrations ranging from 500 to 18,000 µg·L−1. The degradation products were investigated by high-performance liquid chromatography/mass spectrometry (LC–MS/MS), and the toxicity was evaluated against L-929 cell line. The results showed that the laccase activity of 1100 U·L−1 completely degraded etoposide in 60 min, and even the laccase activity of 55 U·L−1 could remove 86% of the etoposide after 360 min. Laccase also degraded etoposide in all evaluated pHs, even in conditions similar to wastewater treatment plants (pH 6 and 7). The biocatalysis followed a first-order kinetics behavior and the degradation kinetics constant was k = 0.0477 min−1. The mass spectroscopy suggested that the degradation mechanism of etoposide was by dehydration and demethylation. Furthermore, laccase degraded etoposide to a non-toxic bio-product in which all tested concentrations show no reduction in metabolic activity of the tested cell line. The results of the etoposide degradation strongly suggested that laccase shows the potential to remove anticancer drugs in wastewater treatment plants. [ABSTRACT FROM AUTHOR]

Secondary acute myeloid leukemia (sAML) may develop following a prior therapy or may evolve from an antecedent hematological disorder such as Fanconi Anemia (FA). Pathophysiology of leukemic evolution is not clear. Etoposide (Eto) is a chemotherapeutic agent implicated in development of sAML. FA is an inherited bone marrow (BM) failure disease characterized by genomic instability and xenobiotic susceptibility. Here, we hypothesized that alterations in the BM niche may play a critical/driver role in development of sAML in both conditions. Expression of selected genes involved in xenobiotic metabolism, DNA double-strand break response, endoplasmic reticulum (ER) stress, heat shock response and cell cycle regulation were determined in BM mesenchymal stem cells (MSCs) of healthy controls and FA patients at steady state and upon exposure to Eto at different concentrations and in recurrent doses. Expression of CYPA1, p53, CCNB1, Dicer1, CXCL12, FLT3L and TGF-Beta genes were significantly downregulated in FA-MSCs compared with healthy controls. Eto exposure induced significant alterations in healthy BM-MSCs with increased expression of CYP1A1, GAD34, ATF4, NUPR1, CXCL12, KLF4, CCNB1 and nuclear localization of Dicer1. Interestingly, FA-MSCs did not show significant alterations in these genes upon Eto exposure. As opposed to healthy MSCs DICER1 gene expression and intracellular localization was not altered on FA BM-MSCs after Eto treatment. These results showed that Eto is a highly potent molecule and has pleiotropic effects on BM-MSCs, FA cells show altered expression profile compared to healthy controls and Eto exposure on FA cells shows differential profile than healthy controls. [ABSTRACT FROM AUTHOR]

The aim of this randomized clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m2, days 8–28; the dose of ATRA was reduced to 45 mg/m2, days 8–10 and 15 mg/m2, days 11–28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1–7 and etoposide 100 mg/day, p.o. or i.v., days 1–3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64–92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010). [ABSTRACT FROM AUTHOR]

C–C motif chemokine ligand 2 (CCL2) is a monocyte chemoattractant that promotes metastatic disease and portends a poor prognosis in many cancers. To determine the potential of anti-CCL2 inhibition as a therapy for recurrent metastatic disease in neuroblastoma, a mouse model of minimal residual disease was utilized in which residual disease was treated with anti-CCL2 monoclonal antibody with etoposide. The effect of anti-CCL2 antibody on neuroblastoma cells was determined in vitro with cell proliferation, transwell migration, and 2-dimensional chemotaxis migration assays. The in vivo efficacy of anti-CCL2 antibody and etoposide against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient-derived xenograft (PDX) in immunodeficient NOD-scid gamma mice. In vitro, anti-CCL2 antibody did not affect cell proliferation but significantly inhibited neuroblastoma cell and monocyte migration towards an increasing CCL2 concentration gradient. Treatment of mice with anti-CCL2 antibody combined with etoposide significantly increased survival of mice after resection of primary tumors, compared to untreated mice. [ABSTRACT FROM AUTHOR]

The pharmacological activity of granulocyte CSF (G-CSF) immobilized using electron-beam synthesis nanotechnology (imG-CSF) was evaluated in an experimental model of ovarian reserve depletion. The effectiveness of the drug was compared with that of its unmodified form. Depletion of the ovarian follicular pool in female Sprague-Dawley rats was caused by a single intravenous injection of the antitumor drug etoposide in the maximum tolerated dose. The effectiveness of the studied drugs was assessed by serum concentration of anti-Mullerian hormone (AMH) measured by ELISA and by the number of primordial, two-layer, multilayer, and atretic follicles counted on serial sections of the ovaries (5-μm thick; through the entire organ) stained with hematoxylin and eosin. It was found that imG-CSF prevents depletion of the ovarian reserve in the model used, which was confirmed by high AMH concentration and higher numbers of primordial, two- and multilayer follicles in comparison with the corresponding parameters in the control (etoposide), and by a decrease in the severity of atretic processes. Unmodified form of the drug demonstrated lower efficiency. [ABSTRACT FROM AUTHOR]

The review is focused on the etoposide delivery systems based on colloidal carriers, i.e., nanoparticles and micelles made of synthetic and natural polymers. Etoposide, a topoisomerase II inhibitor, occupies an important place in the chemotherapy of a number of tumors; however, its use is often limited due to severe side effects. The application of colloidal delivery systems makes it possible to change the pharmacokinetic parameters of etoposide and increase its accumulation in tumors leading to an increase in the antitumor effect. Of particular interest are stimuli-sensitive systems that respond to specific conditions in the tumor microenvironment, which can significantly increase the selectivity of the drug. [ABSTRACT FROM AUTHOR]

The aim of this randomized clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1-mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m2, days 8–28; the dose of ATRA was reduced to 45 mg/m2, days 8–10 and 15 mg/m2, days 11–28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1–7 and etoposide 100 mg/day, p.o. or i.v., days 1–3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64–92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm (p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010). [ABSTRACT FROM AUTHOR]

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is part of the treatment strategy for some patients with high-risk lymphoma by improving survival with an acceptable toxicity profile. Although the BEAM (BCNU, etoposide, cytarabine, and melphalan) intensification regimen is the most used, the optimal dosing for each drug is unclear. Here, we retrospectively compared the outcome of 110 patients receiving higher (400 mg/m2, n = 69) or lower (200 mg/m2, n = 41) etoposide and cytarabine doses in our institution between 2012 and 2019. Patients in the BEAM 200 group experienced less toxicity with reduced fever duration (P < 0.001), number of platelet transfusions (P = 0.008), antibiotic duration (P < 0.001), antifungal therapy (P < 0.001), and mucositis (P < 0.001) whereas length of stay, admission to the intensive care unit, and in-hospital mortality were not different between groups. Progression-free survival (PFS) was non-significantly lower in the BEAM 200 group (36-month PFS, 68% vs. 80%, P = 0.053) whereas OS was similar between the two groups (36-month OS, 87% vs. 91%, respectively, P = 0.12). Albeit a non-significant reduction in PFS, BEAM 200 conditioning intensity was associated with a reduced toxicity profile. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the project was to evaluate intra-CSF etoposide administration in a palliative setting for children and young people with relapsed/refractory central nervous system (CNS) tumours, with the primary endpoints being overall survival and progression-free survival time. A safety endpoint was to assess the side effect profile and complications of intra-CSF etoposide. Methods: Thirty-five patients under the age of 30 years (median age: 5.33 years) were enrolled onto the project. The cross-centre study was a service evaluation, with a data collection spreadsheet designed in Nottingham and completed by both Nottingham and Oxford centres. Data was analysed using SPSS, assessing the overall survival and progression-free survival times, as well as the 6-month and 1-year survival rates. Results: The median overall survival and progression-free survival times were 10.97 and 5.91 months, respectively. The 6-month and 1-year overall survival rates were 67% and 48%, and the progression-free survival rates were 50% and 22%. Age at the start of intra-CSF therapy was significantly associated with overall survival (P = 0.046), with the 6 + age group having improved overall survival. Treatment type was significantly associated with overall survival (P = 0.012), with etoposide intra-CSF treatment being associated with improved overall survival. Treatment duration was significantly associated with both overall survival (P < 0.001) and progression-free survival (P < 0.001). Conclusion: Intra-CSF etoposide treatment has shown to increase both overall and progression-free survival significantly, whilst having few side effects and maintaining a good quality of life for patients, reflecting it as a beneficial therapy in the palliative setting. [ABSTRACT FROM AUTHOR]

Background: Programmed death-ligand 1 (PD-L1) inhibitor plus platinum–etoposide chemotherapy is used as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), regardless of age. Objective: We examined the role of the Geriatric 8 (G8) screening tool for evaluating treatment outcomes in patients with ES-SCLC treated with PD-L1 inhibitor plus platinum–etoposide chemotherapy as first-line therapy. Patients and Methods: Between September 2019 and October 2021, we prospectively evaluated patients with ES-SCLC treated with immunochemotherapy at ten institutions in Japan. The G8 score was assessed before treatment initiation. Results: We evaluated 44 patients with ES-SCLC. Patients with G8 score > 11 had longer overall survival (OS) than those with G8 score ≤ 11 (not reached versus 8.3 months; log-rank test, p = 0.005). In univariate and multivariate analyses, G8 score > 11 [hazard ratio (HR) 0.34; 95% confidence interval (CI) 0.15–0.75; p = 0.008 and HR 0.34; 95% CI 0.14–0.82; p = 0.02, respectively) and performance status (PS) of 2 (HR 5.42; 95% CI 2.08–14.2; p < 0.001 and HR 6.94; 95% CI 2.25–21.4; p < 0.001, respectively) were independent prognostic factors for OS. Among patients with good PS (0 or 1), the OS in patients with G8 score > 11 was significantly longer than that in patients with G8 score ≤ 11 (not reached versus 12.3 months; log-rank test, p = 0.02). Conclusions: G8 score evaluation before treatment initiation was useful as a prognostic factor for ES-SCLC patients who received PD-L1 inhibitors and platinum–etoposide chemotherapy, even with good PS. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy-induced neutropenia (CIN) is a dose-limiting factor for cytotoxic chemotherapy, but recently, it was suggested that CIN contributes to prolonged survival. In this study, we examined the association between severe CIN and survival and determined whether CIN affected survival in patients with extensive-stage small cell lung cancer (ES-SCLC). Methods: The medical records from 214 patients with ES-SCLC treated with etoposide or irinotecan in combination with cisplatin (EP/IP) between 2012 and 2016 were collected and retrospectively analyzed. Landmark analysis was performed at the end of cycle 4, and the relationship between severe CIN and survival was determined by a log-rank test. In addition, a multivariate analysis using the COX proportional hazard model was performed to identify independent predictive factors. The Landmark analysis included 102 patients in the IP group and 47 patients in the EP group. Results: No significant difference was found between grades 0–3 and grade 4 neutropenia and overall survival (OS) in the EP group (P = 0.57). Contrariwise, for the IP patients, the median OS was 444 days for grades 0–3 and 633 days for grade 4 neutropenia, which was significantly longer for patients who developed grade 4 neutropenia (P = 0.03). Multivariate analysis adjusted for potential factors revealed that the development of grade 4 CIN was identified as a significant predictor of longer OS (hazard ratio [HR], 0.50; 95% confidence interval (CI), 0.28–0.87, P = 0.015). Conclusion: The results indicated that the development of severe CIN with IP therapy is associated with prolonged OS. [ABSTRACT FROM AUTHOR]

We performed a single-center, prospective trial to investigate the efficacy of PEG- asparaginase combined with liposomal doxorubicin, etoposide, and methylprednisolone (L-DEP) as an initial therapy for Epstein-Barr virus driven hemophagocytic lymphohistiocytosis (EBV-HLH). None of the patients received any chemotherapy after the diagnosis of EBV-HLH between September 2019 and September 2021. The efficacy was evaluated 2 weeks and 4 weeks after initiating L-DEP primary therapy. Forty-seven eligible patients with EBV-HLH were enrolled. The overall response rate (ORR) was 80.9% (38/47, 12 in clinical CR, 26 in clinical PR) at 2 weeks after the L-DEP regimen; at 4 weeks, the ORR was 75.6% (34/45, 21 in clinical CR, 13 in clinical PR). EBV-DNA loads in blood and plasma were significantly decreased 2 and 4 weeks after the L-DEP regimen (P < 0.001). Ferritin, soluble CD25 (sCD25), triglycerides (TGs), and ultrasonic spleen longitude, and thickness were all decreased significantly 2 and 4 weeks after the L-DEP regimen (P < 0.001). Thus, the L-DEP regimen is an effective initial therapy for EBV-HLH. However, the L-DEP regimen was poor in terms of long-term prognosis and that allo-HSCT should be received as soon as possible once a complete response is achieved. [ABSTRACT FROM AUTHOR]

Background: Etoposide remains the cornerstone of symptomatic management of critically ill patients with secondary hemophagocytic syndrome (sHS). Risk of healthcare-associated infections (HAIs) in this setting with etoposide has never been assessed. We sought to evaluate the association between etoposide administration, HAIs occurrence and survival in critically ill adult patients with sHS. In this retrospective single-center study conducted in a university hospital ICU between January 2007 and March 2020, all consecutive patients with sHS were included. HAIs were defined as any microbiologically documented infection throughout ICU stay. Competing risk survival analysis was performed to determine factors associated with HAIs. Propensity score-based overlap weighting was performed to adjust for factors associated with etoposide use. Results: 168 patients with a median age of 49 [38, 59] were included. Forty-three (25.6%) patients presented with at least 1 microbiologically documented HAI throughout ICU stay. After adjustment, cumulative incidence of HAI was higher in patients receiving etoposide (p = 0.007), while survival was unaffected by etoposide status (p = 0.824). By multivariable analysis, etoposide treatment was associated with a higher incidence of HAIs (sHR 3.75 [1.05, 6.67]), whereas no association with survival (sHR 0.53 [0.20, 1.98]) was found. Other factors associated with increased mortality after adjustment included age, immunodepression, male sex, SOFA score > 13, and occurrence of HAI. Conclusions: In patients with sHS, etoposide treatment is independently associated with increased occurrence of HAIs, whereas no association with survival was found. Intensivists should be aware of increased infectious risk, to promptly detect and treat infections in this specific setting. Studies to assess benefits from prophylactic anti-infectious agents in this setting are warranted and the lack of benefit of etoposide on survival needs to be interpreted cautiously. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous, life-threatening clinical syndrome. There are scarce data on the quality of care in HLH or data comparing treatment patterns and outcomes between different triggers. We aimed to examine quality-of-care indicators and outcomes in adults with various HLH triggers. In this multi-centre retrospective cohort study of adult HLH in the province of Alberta, Canada (1999-2019), we examined quality indicators including diagnostic testing, time to diagnosis and treatment and trigger identification. We also compared treatment regimens and outcomes across HLH triggers. Logistic regression was used to identify predictors of etoposide use. Overall survival (OS) was estimated using the Kaplan-Meier method. We identified 97 patients; 66 (68%) were male. Triggers included malignancy (36%), infection (35%), autoimmune disease (21%) and idiopathic/others (8%). Specialized tests such as sCD25 (53%) and natural killer degranulation assay (19%) were under-performed, as were testing for infectious triggers. Etoposide was administered in only 33 (34%). Neutropenia, hyperbilirubinemia and hyperferritinemia, but not age, sex and comorbidities, were significant predictors of etoposide use. At median follow-up of 32 months, median OS was 18.8 months. Worse OS was seen in malignancy-associated and idiopathic HLH (log-rank P < 0.001). Our study showed low rates of specialized testing such as sCD25 and a low rate of etoposide use. Development of a standardized provincial protocol has the potential to improve quality of care in adult HLH. [ABSTRACT FROM AUTHOR]

Natural killer (NK)/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHLH) is a rare and life-threatening disorder. Its clinical characteristics and appropriate treatment options are unclear. This study aimed to investigate the clinical characteristics and treatment options for this disease. We retrospectively analyzed the clinical data of 84 patients with NK/T-cell lymphoma and compared the characteristics, treatment, and survival between patients with and without HLH. Patients in the NK/T-LAHLH group were more likely to be younger age and have hepatosplenomegaly, B symptoms, neutropenia, anemia, thrombocytopenia, elevated lactate dehydrogenase levels, reduced serum albumin levels, bone marrow involvement, Ann Arbor stage III/IV, and International Prognostic Index score ≥ 3. After multivariate analysis, it was found that elevated lactate dehydrogenase and Ann Arbor stage III/IV were risk factors for HLH in patients with NK/T-cell lymphoma. After 2 weeks of therapy, 78.6% (11/14) patients who received the L-DEP/DEP regimen achieved an overall response rate of HLH, which was higher than that in 42.9% (9/21) patients who received the VP-16 + dexamethasone-based regimen. NK/T-LAHLH patients had poorer survival than non-HLH-NK/TCL patients. For NK/T-LAHLH, the L-DEP/DEP regimen may have a better response rate than the VP-16 + dexamethasone-based regimens. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we modified the classical regimen of the hemophagocytic lymphohistiocytosis-04 protocol and evaluated the efficacy and safety of short-term, low-dose etoposide in patients with refractory macrophage activation syndrome (MAS) associated with adult-onset Still's disease (AOSD). Methods: A total of 17 patients with refractory AOSD-associated MAS were enrolled and received short-term, low-dose etoposide (100 mg twice a week for four times). Another 11 patients, who were not treated with etoposide, were included as historical controls. Patient information, such as clinical manifestations, laboratory results, treatments, and short-term prognosis, were recorded and analyzed. Results: In this case series, 88.24% of the patients with MAS who were treated with short-term, low-dose etoposide had a favorable response in 3 weeks, which was significantly higher (p = 0.017) than that in the patients with MAS who were treated without etoposide (45.45%). The 90-day survival rate after the onset of MAS was significantly higher (p = 0.0029) among the patients in the short-term etoposide group (16/17, 94.12%) than in the control group (5/11, 45.45%). Conclusion: The regimen of short-term (2 weeks), low-dose etoposide was highly effective in the treatment for patients with refractory AOSD-associated MAS with an acceptable safety profile. Key Points • There is no high level evidence to guide the management of refractory MAS-associated AOSD patients. • This study was the first to propose and confirm the efficacy and safety of short-term, low-dose etoposide in the treatment of refractory MAS-associated AOSD patients. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend etoposide, methotrexate, actinomycin D (EMA)/cyclophosphamide, vincristine (CO) as first-line treatment for high-risk gestational trophoblastic neoplasia (GTN). However, the floxuridine, actinomycin D, etoposide and vincristine (FAEV) regimen is commonly used to treat these patients in China. We conducted a randomised controlled trial to compare the efficacies and toxicities of FAEV and EMA/CO.Methods: Ninety-four patients with GTN were enrolled between May 2015 and April 2019 and randomly assigned to the FAEV or EMA/CO regimen. The rates of complete remission and relapse and the toxicities were compared in August 2021.Results: Five patients were excluded from the analysis. There were 46 patients in the FAEV group and 43 patients in the EMA/CO group. The complete remission rates following primary treatment were 89.1% and 79.1% (P = 0.193), respectively. The relapse rates were 8.7% and 9.3% (P = 0.604). The apparent incidences of grade 4 myelosuppression were 60.9% and 32.6% (P = 0.008), respectively; however, they became both 32.6% (P = 0.996) after granulocyte colony-stimulating factor support. Other adverse reactions were similar in the two groups. No patient died of disease.Conclusion: FAEV has comparable efficacy and toxicity to EMA/CO as the primary treatment for high-risk GTN, and may thus be another first-line choice of chemotherapy.Clinical Trial Registration: chictr.org.cn: ChiCTR1800017423. [ABSTRACT FROM AUTHOR]

Tight regulation of immediate early gene (IEG) expression is important for synaptic plasticity, learning, and memory. Recent work has suggested that DNA double strand breaks (DSBs) may have an adaptive role in post-mitotic cells to induce IEG expression. Physiological activity in cultured neurons as well as behavioral training leads to increased DSBs and subsequent IEG expression. Additionally, infusion of etoposide—a common cancer treatment that induces DSBs—impairs trace fear memory. Here, we assessed the effects of hippocampal infusion of 60 ng of etoposide on IEG expression, learning, and memory in 3–4 month-old C57Bl/6J mice. Etoposide altered expression of the immediate early genes cFos and Arc in the hippocampus and impaired hippocampus-dependent contextual fear memory. These data add to the growing evidence that DSBs play an important role in IEG expression, learning, and memory, opening avenues for developing novel treatment strategies for memory-related disorders. [ABSTRACT FROM AUTHOR]

Chemotherapy combined with radiotherapy could reduce the risk of recurrence in early-stage extranodal NK/T lymphoma (ENKTL). However, the optimal combined chemotherapy regimen is still unknown. Our previous study reported that LVDP (l-asparaginase, etoposide, dexamethasone, and cisplatin) combined with radiotherapy was a potentially effective and safe treatment regimen for early-stage ENKTL. This study further validated the efficacy and safety of LVDP chemotherapy combined with radiation for early-stage ENKTL with more patients and longer follow-up. We retrospectively studied 112 patients with early-stage ENKTL from September 2010 to September 2019. All patients received the LVDP regimen, and 101 of them received radiotherapy. The patients' characteristics, treatment responses, survival outcomes, prognostic factors, and toxicities were analyzed. The median follow-up was 60 months (range, 4 to 117). All patients received median 4 cycles of the LVDP chemotherapy. At the end of therapy, the objective response rate and complete response rate were 88.3% and 77.6%, respectively. The 3- and 5-year OS were 79.6% and 73.2%, and the 3- and 5-year PFS were 75.4% and 71.6%, respectively. Among them, the LVDP regimen combined with radiotherapy yielded more favorable treatment outcomes (the 3-year OS and PFS were 83.1% and 80.8%). The most common severe hematologic toxicity was leukopenia (25% grade 3/4), and the most common severe non-hematologic toxicity was increased transaminase (4.5% grade 3/4). No pancreatitis or treatment-related death occurred. The LVDP regimen combined with radiotherapy had a good therapeutic response and long-term survival with tolerable toxicity for patients with early-stage ENKTL. [ABSTRACT FROM AUTHOR]

Ten 4β-N-substituted derivatives of 4′-O-demethylpodophyllotoxin were designed by aldehydes reacting with 4′-O-demethylpodophyllotoxin. Their cytotoxicity against cancer cell lines (HeLa) was evaluated using the MTT assay. Compounds 7a–7d, 7f, 7g, and 7h exhibited pronounced stronger activity than that of the positive control etoposide (VP-16). 4β-N-Substituted derivatives of 4′-O-demethylpodophyllotoxin were worthy of further study with potential antitumor activity. [ABSTRACT FROM AUTHOR]

Purpose: Oncolytic virotherapy is emerging as an important modality in cancer treatment. In a previous study, we designed and constructed Ad-Apoptin-hTERTp-E1a (Ad-VT), a dual cancer-selective anti-tumor recombinant adenovirus. Methods: To explore the therapeutic effect of recombinant adenovirus Ad-VT together with Etoposide on small cell lung cancer, the ability of Ad-VT alone, Etoposide alone, and a combination of Ad-VT + Etoposide to inhibit proliferation of NCI-H446 and BEAS-2B cells was investigated using the WST-1 method. According to the inhibitory action of different combinations, a combination index (CI) was estimated by CalcuSyn software to select the best combination. The inhibitory effect of Ad-VT combined with Etoposide on NCI-H446 and BEAS-2B cells was detected by crystal violet staining and the CFST method. Hoechst, Annexin V and JC-1 staining were used to explore the inhibitory pathway of Ad-VT combined with Etoposide on NCI-H446 cells. The migratory and invasive abilities of treated NCI-H446 cells were assessed by Transwell and BioCat methods. Tumor volume, body weight and survival rate were measured to analyze the anti-tumor and toxic effects of different treatments in tumor-bearing mice. Results: Ad-VT (20 MOI) combined with Etoposide (400 nM) significantly inhibited NCI-H446 cell proliferation with reduced toxicity of Etoposide to normal cells. Ad-VT induced apoptosis of NCI-H446 cells mainly through the mitochondrial apoptosis pathway, an effect significantly increased by the combined treatment. Ad-VT together with Etoposide significantly inhibited migration and invasion of NCI-H446 cells, inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. Conclusions: The above results indicate that when combined with Etoposide, Ad-VT may have an important role in synergistically inhibiting tumors. [ABSTRACT FROM AUTHOR]

Background: Patients with small-cell lung cancer (SCLC) have a dismal prognosis with limited overall survival (OS) despite a high response rate to chemotherapy. Recently, immune checkpoint inhibitors, combined with chemotherapy, as the first-line treatment for extensive-stage (ES)-SCLC have shown improvement in clinical outcomes. Patients and methods: Real-world data from 68 Korean ES-SCLC patients, treated with atezolizumab, etoposide, and carboplatin at Yonsei Cancer Center between June 2019 and November 2020, were retrospectively analyzed to determine safety and efficacy using Cox regression analysis. Results: The median follow-up was 11.6 months. The median progression-free survival was 4.6 months (95% confidence interval [CI] 4.0–5.2), and the median OS was 12.0 months (95% CI 7.4–16.6). Baseline bone metastasis, immune-related adverse events (IRAEs), and elevated LDH were related to OS (hazard ratio 2.18, 0.33, and 4.64; P = 0.05, 0.02, and 0.003, respectively). Among the 42 patients with disease progression, liver metastasis progression and baseline bone metastasis were associated with inferior OS, but without statistical significance (hazard ratio 2.47 and 1.97; P = 0.25 and 0.26, respectively). Overall, 61 (89.7%) patients experienced treatment-related adverse events (TRAEs), with hematologic toxicities as the most common grade 3–4 TRAEs. Twenty-two (32.4%) patients experienced IRAEs, with skin rash as the most common, and five (7.4%) patients had grade-3 IRAEs (pneumonitis, hyperglycemia, and aspartate aminotransferase elevation). Conclusion: Atezolizumab, combined with etoposide and carboplatin, showed efficacy and safety in our real-world data. Further studies are needed to predict the response to immunotherapy in SCLC. [ABSTRACT FROM AUTHOR]

A new series of 1,3,4-oxadiazole incorporated imidazo[1,5-a]pyridine derivatives was prepared. Anticancer activity of all the obtained compounds was investigated by employing MTT assay. Among them, six compounds showed most prominent anticancer activity than etoposide. [ABSTRACT FROM AUTHOR]

Background: Adrenocortical carcinoma (ACC) is a rare and aggressive disease that is often diagnosed at an advanced stage. There is no standard treatment for metastatic ACC; EDP-M (etoposide, doxorubicin, and cisplatin plus mitotane) is one treatment option. A randomized controlled trial (FIRM-ACT) evaluating the efficacy of EDP-M showed progression-free survival (PFS) was 5.0 months, overall survival (OS) was 14.8 months, the response rate was 19%, and adrenal insufficiency occurred in 3.4% of patients. However, the efficacy and safety of this regimen in Asia are not fully reported. Methods: We retrospectively analyzed 43 patients diagnosed with metastatic ACC at the National Cancer Center Hospital between 1997 and 2020. We evaluated PFS, OS, and response in 17 patients who received EDP-M as first-line therapy. Results: The median age at treatment initiation was 45 years (range 18–74). Eight patients (47%) had autonomous hormone production, including six patients with hypercortisolism. The best response of partial response and stable disease was seen in two (12%) and ten (59%) patients, respectively. The median PFS was 6.2 months [95% confidence interval (CI): 4.3–10.0]. The median OS was 15.4 months (95% CI 11.6–not reached). Three patients received only one cycle due to adverse effects associated with hypercortisolism. Grade 3/4 adverse events associated with adrenal insufficiency occurred in three (17%) cases, resulting in EDP-M discontinuation. Conclusions: The EDP-M regimen had similar PFS to that observed in FIRM-ACT. Adrenal insufficiency was more frequent in the current study, but this could be managed with supportive endocrinological care such as cortisol replacement. [ABSTRACT FROM AUTHOR]

Micronucleus (MN) assessment is a valuable tool in safety assessment. However, several compounds are positive in the in vivo bone marrow (BM) MN assay but negative in vitro, reflecting that BM complexity is not recapitulated in vitro. Importantly, these compounds are not genotoxic; rather, drug-driven pharmacological-effects on the BM increase MN, however, without mechanistic understanding, in vivo positives stop drug-progression. Thus, physiologically-relevant BM models are required to bridge the gap between in vitro and in vivo. The current study aimed to investigate the utility of two human 3D BM models (fluidic and static) for MN assessment. MN induction following treatment with etoposide and Poly-ADP Ribose Polymerase inhibitor (PARPi) and prednisolone (negative in vitro, positive in vivo) was determined in 2D L5178Y and human BM cells, and the 3D BM models. Etoposide (0–0.070 µM) and PARPi (0–150 µM) induced MN in both 3D BM models indicating their utility for genotoxicity testing. Interestingly, PARPi treatment induced a MN trend in 3D more comparable to in vivo. Importantly, prednisolone (0–1.7 mM) induced MN in both 3D BM models, suggesting recapitulation of the in vivo microenvironment. These models could provide a valuable tool to follow up, and eventually predict, suspected pharmacological mechanisms, thereby reducing animal studies. [ABSTRACT FROM AUTHOR]

Candidemia, one of the most common invasive fungal infections in hospitalized patients, can lead to death and huge financial losses. Candida albicans is the main causative agent of this disorder and Candida glabrata occupies the second or third place, for which new therapeutic alternatives must be found. The objective of the present study was to evaluate the inhibitory effect of etoposide and camptothecin (inhibitors of deoxyribonucleic acid (DNA) topoisomerase) on the C. glabrata CBS138 strain. Etoposide and camptothecin showed better or similar MIC (minimum inhibitory concentration) (5 and 2.5 μg/mL, respectively), with respect to fluconazole (8 μg/mL) and itraconazole (4 μg/mL). They also suppressed colony formation during the 12-h test. On the other hand, petite colonies were less formed by exposing C. glabrata to etoposide or camptothecin (indicating low toxicity), with respect fluconazole and itraconazole. Such colonies are phenotypically observed as limited growth in medium containing a non-fermentable carbon source, and are genotypically characterized by a partial or total loss of mitochondrial DNA (mtDNA) fragments. Using PCR techniques and cell staining with 4′,6-diamidino-2-phenylindole (DAPI), loss of mtDNA was detected only in yeast cells treated with fluconazole. Additionally, molecular docking studies with etoposide and camptothecin showed recognition in the active site of the Topo I and II enzymes from C. glabrata. Since etoposide and camptothecin showed good inhibitory activity and low toxicity on C. glabrata; they should certainly be of interest for the treatment of C. glabrata infections and the design and development of new antifungal compounds derived from these drugs. [ABSTRACT FROM AUTHOR]

Gallbladder neuroendocrine carcinomas (GB-NECs) are a group of rare and heterogeneous neoplasms. There are few reports regarding laparoscopic surgery for GB-NEC cases diagnosed at advanced stage. Three patients, two females and one male, were admitted to our hospital. Two patients had the chief complaint of upper quadrant pain and one patient was found to have gallbladder occupation during a routine health checkup. No patient complained of jaundice, weight loss, or carcinoid syndrome–related symptoms including diarrhea, edema, flushing, and wheezing. Contrast-enhanced computed tomography (CT) examination showed local wall thickening of the gallbladder. In addition, one patient showed focal liver parenchymal invasion, and none of the three patients' preoperative imaging examination revealed lymph node (LN) metastases. All three patients underwent laparoscopic radical cholecystectomy according to intraoperative frozen pathological examination, and they were diagnosed as GB-NEC based on postoperative pathology and immunohistochemistry. TNM stages of these patients were IIIA (T3N0M0), IIIB (T3N1M0), and IVB (T3N2M0), respectively. Chromogranin A (CgA) and synaptophysin (Syn) were positive in all cases. No patient encountered postoperative bleeding, bile leakage, abdominal abscess, gastrointestinal fistulas, or pulmonary complication. Two patients underwent postoperative chemotherapy with two cycles and seven cycles of etoposide plus cisplatin, respectively. Another patient did not receive postoperative chemotherapy due to his poor general condition. The overall survival time of the three patients was 4.6 months, 16.8 months, and 8.5 months, respectively. All three patients presented with liver and/or bile duct recurrence after surgery with a tumor-free survival time of 2.3 months, 3.3 months, and 3.0 months, respectively. Laparoscopic surgery may be considered a potential treatment for advanced GB-NEC in selected patients. However, further studies are needed to investigate the tumor-free survival benefit of laparoscopic surgery, and whether expanding the resection scope could reduce postoperative recurrence. [ABSTRACT FROM AUTHOR]

Pyoderma gangrenosum (PG) is an uncommon, serious, ulcerating skin disease of uncertain etiology. It manifests as a noninfectious, progressive necrosis of the skin characterized by sterile neutrophilic infiltrates. It seems to be a disorder of the immune system. PG is associated with certain underlying conditions in at least 50% of cases. Therefore, it is important to look carefully for comorbidities in every patient with PG and treat them adequately to improve the prognosis. Here, we demonstrate a 35-year-old man diagnosed with multifocal PG and hemophagocytic lymphohistiocytosis (HLH) with fatal outcome, despite combined, long-term, intensive dermatological and hematological treatment with high doses of steroids, cyclosporin, intravenous immunoglobulins (IVIG), HLH-2004 protocol with intravenously administered etoposide, and anakinra. This case is presented owing to the extremely rare coexistence of PG and HLH and the related diagnostic and therapeutic difficulties. It is also worth underlying that the diagnosis of HLH should perhaps be considered in the presence of a high percentage of double-negative T lymphocytes (DNTs) in flow cytometry, after excluding the diagnosis of lymphoma and leukemia. In this article we have also performed and present the critical literature review of local and systemic options in the management of PG lesions based on a detailed search of the PubMed database. [ABSTRACT FROM AUTHOR]