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Summary: A chemotherapy‐based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single‐arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18–75 years. The EAP regimen consisted of etoposide 75 mg/m2/day on days 1–2, cytarabine 300 mg/m2 every 12 h on days 1–2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1–92.7) × 106/kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2–3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma. [ABSTRACT FROM AUTHOR]

AbstractA phase 1b study was conducted to evaluate the safety and feasibility of ciprofloxacin and etoposide combination treatment in subjects with relapsed and refractory acute myeloid leukemia. Eleven subjects were enrolled in the study. Utilizing the standard ‘3 + 3’ design, escalating ciprofloxacin doses (750 mg, 1000 mg) twice daily on D1-D10 in combination with a fixed dose (200 mg) of etoposide on D2-D8 were administered. Maximum tolerated dose was determined to be 1000 mg of ciprofloxacin in combination with 200 mg of etoposide. Serious adverse events occurred in 54.5% (n = 6) subjects and 91% (n = 10) subjects reported ≥ grade 3 toxicities. Nine subjects completed treatment, one had a dose-limiting toxicity, and one withdrew. One subject achieved complete remission with a duration of 111 days and one subject achieved morphologic leukemia-free state after cycle 1. While the combination demonstrated safety and an acceptable toxicity profile, only modest hematologic and clinical benefits were observed.This trial was registered at www.clinicaltrials.gov as #NCT02773732. [ABSTRACT FROM AUTHOR]

Objective: To investigate the outcomes of robot-assisted radical cystectomy, intracorporeal urinary diversion, and extended lymph node dissection in patients with muscle-invasive bladder cancer who underwent neoadjuvant chemotherapy. Materials and Methods: A total of 14 patients underwent neoadjuvant chemotherapy for invasive bladder tumors, followed by robot-assisted radical cystectomy, extended lymph node dissection, and intracorporeal urinary diversion. Demographic, operative, and postoperative information of the patients was retrospectively evaluated. Gemcitabine plus cisplatin and cisplatin plus etoposide regimens were used as neoadjuvant treatments. Early and late-term complications were recorded. Results: In the early postoperative period (0-30 days), Clavien-Dindo grade 2 complications occurred in 6 patients and grade 3 complications in 2 patients. In the late postoperative period (31-90 days), Clavien-Dindo grade 2 complications occurred in 1 patient and grade 3 complications in 1 patient. The mean follow-up period was 15.5±5.7 months. Conclusion: Although the intracorporeal technique is more demanding in terms of learning and use, preoperative chemotherapy application should not be seen as a limitation in the application of this technique. [ABSTRACT FROM AUTHOR]

Etoposide (EPT) offers significant benefits in the tumor therapy domain. EPT may cause ferroptosis in lung cancer cells; however, its limited bioavailability and low water solubility inhibit its potential applications. Therefore, we investigated the properties of EPT-loaded folic acid clocked with mesoporous silica nanoparticles (MSNs) (FA-MSN@EPT) that target lung tumor cells. We assessed the capacities of MSN@EPT and FA-MSN@EPT to induce ferroptosis in lung cancer cells by measuring ferroptosis-related ferritin (Fe2+), malondialdehyde, and glutathione levels. Enhanced ferroptosis, inhibition of A549 and H1299 cell proliferation, migration, invasion, and considerable improvements in the EPT bioavailability were noted when the fabricated MSN@EPT and FA-MSN@EPT were utilized. Furthermore, the apoptotic mode of cell death was investigated by acridine orange and ethidium bromide (AO-EB) and 4′,6-diamidino-2-phenylindole (DAPI) staining and flow cytometry using annexin V-FITC and propidium iodide staining. This opens new possibilities for the clinical treatment of various tumors and offers a possible therapeutic option for lung cancer. [Display omitted] • We fabricated etoposide-loaded folic-acid-clocked mesoporous nanoparticles (NPs). • NPs to induce ferroptosis in lung cancer cells by measuring ferroptosis-related assays. • Enhanced ferroptosis, inhibition of A549 and H1299 cell proliferation, and migration of the NPs. • Apoptosis was investigated by biochemical staining and flow cytometry. [ABSTRACT FROM AUTHOR]

Sinonasal teratocarcinosarcomas (SNTCS) are rare sinonasal malignancies, the incidence of which is less than 1% of all tumors. There is limited data available on SNTCS's, often as case reports and small case series. The management of SNTCS is complicated because of its location, locally aggressive biology, difficulty in achieving complete resection, and limited data on chemotherapy in these malignancies. This audit was performed to understand the role of neoadjuvant chemotherapy (NACT) in SNTCS's, its ability to downstage the disease, achieve complete resection, and impact on long-term survival outcomes. This was a retrospective analysis of a prospectively maintained database approved by the Institutional Ethics Committee (IEC). The baseline characteristics, the extent of tumor, Kadish stage, NACT regimen, and adverse events were extracted from the Electronic Medical Records and the patient's case file. Patients with baseline extensive/inoperable disease were referred for NACT from the multidisciplinary joint clinic followed by response assessment (RECIST v1.1). Patients underwent skull-base surgery if respectable post-completion of NACT, however, if deemed unresectable were treated with non-surgical modalities or palliative therapies. The data of 27 patients were evaluated from the year 2015–2022. The median age was 42 years (IQR:30–56) and 85.2% (n = 23) were males. The ECOG-PS was 0–1 in 88.8% (n = 24) patients. All 27 patients received NACT in view of extensive disease at presentation. 74.1% (n = 20) patients received Cisplatin-Etoposide and 25.9% (n = 7) received other chemotherapy regimens. The median number of chemotherapy cycles was 2(IQR:2–3). 96.3% patients (n = 26) completed the planned NACT cycles. 70.4% (n = 19) patients achieved a partial response in post-NACT imaging. 77.8% (n = 18) underwent surgery, 18.5% (n = 5) received CTRT, and 7.4% (n = 2) received definitive-RT alone. The median PFS and OS of the cohort was 19months (95%CI:12.0–25.6) and 23months (95%CI:5.94–40.06) respectively. NACT is safe, feasible, and effective with significant response rates, leading to effective downstaging, resectability and improved survival in patients with locally advanced SNTCS's. • Sinonasal teratocarcinosarcomas (SNTCS) are rare sinonasal malignancies, the incidence of which is approximately less-than 1% of all tumors. This audit was performed to understand the role of neoadjuvant chemotherapy (NACT) in SNTCS's, its ability to downstage the disease, achieve complete resection, and impact on long-term survival outcomes. • The median PFS and OS of the cohort was 19 months (95%CI:12.0–25.6) and 23 months (95%CI:5.94–40.06), respectively. • NACT is safe, feasible, and effective with significant response rates, leading to effective downstaging, resectability, and improved survival in patients with locally advanced SNTCS's. [ABSTRACT FROM AUTHOR]

Simple Summary: Globally, breast cancer is the most common malignancy and the most frequent cause of cancer-related deaths among women. Chemotherapy is the major systemic treatment for breast cancer, but unfortunately patients often develop resistance, which leads to a poor outcome. Chemotherapy works in a defined manner and this study explores the role of a molecule called insulin-like growth factor binding protein-2 (IGFBP-2), frequently increased by tumours, in the response of cancer cells to chemotherapy. This work suggests that reducing IGFBP-2 has the potential to improve sensitivity to chemotherapy and may provide insight into optimising current treatment strategies. The role if insulin-like growth factor binding protein-2 (IGFBP-2) in mediating chemoresistance in breast cancer cells has been demonstrated, but the mechanism of action is unclear. This study aimed to further investigate the role of IGFBP-2 in the DNA damage response induced by etoposide in MCF-7, T47D (ER+ve), and MDA-MB-231 (ER-ve) breast cancer cell lines. In the presence or absence of etoposide, IGFBP-2 was silenced using siRNA in the ER-positive cell lines, or exogenous IGFBP-2 was added to the ER-negative MDA-MB-231 cells. Cell number and death were assessed using trypan blue dye exclusion assay, changes in abundance of proteins were monitored using Western blotting of whole cell lysates, and localization and abundance were determined using immunofluorescence and cell fractionation. Results from ER-positive cell lines demonstrated that upon exposure to etoposide, loss of IGFBP-2 enhanced cell death, and this was associated with a reduction in P-DNA-PKcs and an increase in γH2AX. Conversely, with ER-negative cells, the addition of IGFBP-2 in the presence of etoposide resulted in cell survival, an increase in P-DNA-PKcs, and a reduction in γH2AX. In summary, IGFBP-2 is a survival factor for breast cancer cells that is associated with enhancement of the DNA repair mechanism. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of advanced-stage Hodgkin lymphoma (HL) is a rapidly evolving field with the introduction of new antibody-mediated drugs to first-line therapies and improving progression-free survival (PFS) to 80–94%. The novel modalities include the anti-CD30 antibody drug conjugate brentuximab vedotin and the anti-PD1 antibody (immune checkpoint inhibitor) that blocks a receptor, helping HL cells to turn off the immune cells, fighting malignant cells. When aggressive therapy is used, a negative result of the interim PET/CT scan can be predictive of a favorable outcome, allowing for a subsequent de-escalation of therapy. A more aggressive therapy is associated with higher short-term and long-term toxicity. Thus, the treatment choice for young patients (median age 30–34 years) should also take into consideration the long-term toxicity, since their expected life longevity exceeds half a century. The current review analyzes the recently published studies that may become practice changing and lead to significantly improved PFS. The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the introduction of the international prognostic scoring (IPS) system; therapeutic decision-making based on both IPS and interim PET/CT data; the finding that a negative interim PET/CT result could be safely used for treatment de-escalation; the introduction of intensive combination chemotherapy like escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin (vincristine), procarbazine, and prednisone); and further modification of this protocol with the incorporation of a conjugated anti-CD30 antibody brentuximab vedotin (BV) into first-line regimens, like BV-AVD (BV+ adriamycin, vinblastine and dacarbazine) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). The accruing data about the toxicity of the escalated BEACOPP protocol have led to decreasing the number of therapeutic cycles, substitution of toxic agents like procarbazine with dacarbazine (e.g., BEACOPDac), and reduction/omission of radiation therapy. Lately, a significant advancement has been made by the integration of checkpoint inhibitors in the first-line treatment, with preliminary results demonstrating the superiority of anti-PD1 combined with chemotherapy (nivolumab-AVD) compared to the BV-AVD regimen. This review aims to analyze recently published studies whose findings could change the treatment practice in advanced-stage HL. [ABSTRACT FROM AUTHOR]

Simple Summary: The evaluation of therapeutic approaches over a decade at a tertiary cancer center in Germany was undertaken due to the frequent and critical discussions surrounding the selection of chemotherapy regimens and the incorporation of prophylactic cranial irradiation (PCI) in the management of limited disease small cell lung cancer (LD-SCLC). We found significant differences in progression-free survival (PFS) and overall survival (OS) between patients treated with carboplatin and etoposide (CP) and those treated with cisplatin and etoposide (EP), with EP showing better outcomes. Concomitant chemotherapy was also associated with improved PFS and OS. Notably, PCI was found to significantly improve OS and showed a trend towards improved PFS. Female patients had better OS, and the type of chemotherapy and PCI remained independent predictors of survival. This research provides valuable insights into treatment patterns, outcomes, and survival predictors for LD-SCLC, emphasizing the importance of personalized treatment approaches and the potential benefits of PCI. However, the study's retrospective nature and sample-size limitations should be considered, highlighting the need for further prospective studies in this field. In this study, we investigated the outcomes and factors influencing treatment efficacy in 93 patients with limited disease small cell lung cancer (LD-SCLC), with a median age of 64 years. We focused on the impact of chemotherapy regimens, prophylactic cranial irradiation (PCI), and patient-related variables. The median follow-up for OS was 17.3 months. We observed a statistically significant difference in PFS between LD-SCLC patients treated with cisplatin and etoposide (EP) and those treated with carboplatin and etoposide (CP) (PFS: EP 13.63 months vs. CP 6.54 months, p < 0.01). Patients treated with EP had better overall survival (OS) than CP-treated patients (OS: EP 26.9 months vs. CP 16.16 months, p < 0.01). Concomitant chemotherapy was associated with improved PFS (p = 0.003) and OS (p = 0.002). Patients receiving PCI showed superior OS (p = 0.05) and a trend towards improved PFS (p = 0.057). Female gender was associated with better OS (p = 0.025). Most patients had an ECOG performance status of 0 (71%). This real-world study underscores the importance of multidisciplinary LD-SCLC management, emphasizing the roles of chemotherapy, radiotherapy, and PCI. These findings inform personalized treatment strategies and emphasize the need for prospective trials to validate these results and optimize LD-SCLC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of neurogenic locus notch homolog protein 1 (NOTCH1)- and nuclear factor erythroid 2-related factor 2 (NRF2)-related pathways is highly heterogeneous in small cell lung cancer (SCLC) and, when they are both abnormally activated, they can synergistically cause neoplastic proliferation. In this paper, we investigate the possible role of KEAP1 silencing in NRF2 and NOTCH axis deregulation in SCLC by evaluating its impact on the modulation of cellular defense systems, cell growth, and differentiation. We also investigate the impact of these systems' impairment in response to conventional chemotherapies and NOTCH inhibitors in silenced SCLC cell lines with different Kelch-like ECH-associated protein 1 (KEAP1) alterations. The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in the resistance of tumor cells against therapeutic drugs. The dysfunction of the KEAP1/NRF2 system has been correlated with neoplastic patients' outcomes and responses to conventional therapies. In lung tumors, the growth and the progression of cancer cells may also involve the intersection between the molecular NRF2/KEAP1 axis and other pathways, including NOTCH, with implications for antioxidant protection, survival of cancer cells, and drug resistance to therapies. At present, the data concerning the mechanism of aberrant NRF2/NOTCH crosstalk as well as its genetic and epigenetic basis in SCLC are incomplete. To better clarify this point and elucidate the contribution of NRF2/NOTCH crosstalk deregulation in tumorigenesis of SCLC, we investigated genetic and epigenetic dysfunctions of the KEAP1 gene in a subset of SCLC cell lines. Moreover, we assessed its impact on SCLC cells' response to conventional chemotherapies (etoposide, cisplatin, and their combination) and NOTCH inhibitor treatments using DAPT, a γ-secretase inhibitor (GSI). We demonstrated that the KEAP1/NRF2 axis is epigenetically controlled in SCLC cell lines and that silencing of KEAP1 by siRNA induced the upregulation of NRF2 with a consequent increase in SCLC cells' chemoresistance under cisplatin and etoposide treatment. Moreover, KEAP1 modulation also interfered with NOTCH1, HES1, and DLL3 transcription. Our preliminary data provide new insights about the downstream effects of KEAP1 dysfunction on NRF2 and NOTCH deregulation in this type of tumor and corroborate the hypothesis of a cooperation of these two pathways in the tumorigenesis of SCLC. [ABSTRACT FROM AUTHOR]

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]

Introduction: Neuroendocrine carcinoma (NEC) is characterized by a poor prognosis and is generally treated with platinum and etoposide combination therapy as first-line chemotherapy. However, it remains uncertain whether carboplatin and etoposide combination therapy (CE) and cisplatin and etoposide combination therapy (PE) have comparable treatment efficacy. In this retrospective analysis, we compared the efficacy and safety of CE and PE in patients with NEC. Methods: We retrospectively reviewed the patient's clinical record from 2005 to 2022 at the Department of Medical Oncology, Tohoku University Hospital. Patients who received either CE or PE were included in the study. Statistical analyses were performed using JMP Pro 16.0 (SAS Institute Inc., Cary, NC, USA). Results: A total of 104 patients were enrolled, with 73 patients assigned to the CE group and 31 patients assigned to the PE group. Statistically, the response rate, progression-free survival time and overall survival time were 42.6%, 5.1 months (95% CI: 3.5–6.3) and 13.6 months (95% CI: 8.9–17.4), respectively, in the CE groups and 44.4%, 5.6 months (95% CI: 3.1–7.0) and 12.5 months (95% CI: 11.2–14.6), respectively, in the PE groups. There was no significant difference in treatment efficacy between the CE and the PE groups. However, the number of patients with elevated creatinine (3.35 mg/dL and 3.88 mg/dL in 2 patients, respectively) was significantly higher in the PE group than in the CE group. Conclusion: The efficacy of CE and PE in patients with NEC is comparable. However, the incidence of renal dysfunction was found to be significantly higher in the PE group than in the CE group. [ABSTRACT FROM AUTHOR]

When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis. [ABSTRACT FROM AUTHOR]

Therapy-related leukemia carries a poor prognosis, and leukemia after chemotherapy is a growing risk in clinic, whose mechanism is still not well understood. Ikaros transcription factor is an important regulator in hematopoietic cells development and differentiation. In the absence of Ikaros, lymphoid cell differentiation is blocked at an extremely early stage, and myeloid cell differentiation is also significantly affected. In this work, we showed that chemotherapeutic drug etoposide reduced the protein levels of several isoforms of Ikaros including IK1, IK2 and IK4, but not IK6 or IK7, by accelerating protein degradation, in leukemic cells. To investigate the molecular mechanism of Ikaros degradation induced by etoposide, immunoprecipitation coupled with LC-MS/MS analysis was conducted to identify changes in protein interaction with Ikaros before and after etoposide treatment, which uncovered KCTD5 protein. Our further study demonstrates that KCTD5 is the key stabilizing factor of Ikaros and chemotherapeutic drug etoposide induces Ikaros protein degradation through decreasing the interaction of Ikaros with KCTD5. These results suggest that etoposide may induce leukemic transformation by downregulating Ikaros via KCTD5, and our work may provide insights to attenuate the negative impact of chemotherapy on hematopoiesis. [ABSTRACT FROM AUTHOR]

• ASCT sequential CD19/22 CART for R/R B-NHL achieved good response rates and long-term survival. • BEAMF regimen before ASCT sequential CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen. • The incidence of adverse events such as grade 2 hypoxemia, peripheral edema, and elevated AST in the BEMAF regimen was higher than that in the BEAM regimen. • The kinetics of CD19 and CD22 CART were similar in the BEAM and BEAMF regimens. The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve outcomes for relapsed or refractory (R/R) B-cell non-Hodgkin-lymphoma (B-NHL). The widely used conditioning regimen before ASCT plus CART therapy reported in the literature was carmustine, etoposide, cytarabine and melphalan (BEAM). However, whether adding fludarabine to the BEAM regimen (BEAMF) can improve the survival of patients with R/R B-NHL remains unknown. In total, 39 and 19 patients with R/R B-NHL were enrolled to compare clinical outcomes in the BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy, respectively. The objective response (OR) rates at 3 months to BEAM and BEAMF regimens before ASCT plus CD19/22 CART therapy were 71.8% and 94.7%, respectively (P = 0.093). The BEAMF regimen showed a trend towards a superior duration of response compared with the BEAM regimen (P = 0.09). After a median follow-up of 28 months (range: 0.93–51.9 months), the BEAMF regimen demonstrated superior 2-year progression-free survival (PFS) (89.5% versus 63.9%; P = 0.048) and 2-year overall survival (OS) (100% vs 77.3%; P = 0.035) compared with the BEAM regimen. In the multivariable Cox regression analysis, OR at month 3 (responders) was remarkably correlated with better OS (hazard ratio: 0.112, P = 0.005) compared with OR (non-responders). For patients with R/R B-NHL, the BEAMF regimen before ASCT plus CD19/22 CART therapy was correlated with superior PFS and OS than the BEAM regimen, and the BEAMF regimen is a promising alternative conditioning regimen for ASCT plus CAR-T therapy. [ABSTRACT FROM AUTHOR]

Tracheomediastinal fistula is a rare but life‐threatening complication of cancer. We report a case of tracheomediastinal fistula induced by concurrent chemoradiotherapy in limited stage small cell lung cancer. Despite the treatment response, the metastatic paratracheal lymph node increased gradually during concurrent chemoradiotherapy, resulting in the occurrence of tracheomediastinal fistula and mediastinitis. Without any surgical intervention, the patient achieved successful recovery from mediastinitis through antibiotic treatment, although the tracheomediastinal fistula remained open. In this report, we also review previous studies of tracheomediastinal and bronchomediastinal fistulas and summarize the clinical features. [ABSTRACT FROM AUTHOR]

Background and purpose: Although recent advances in cancer treatment have increased patient survival and improved quality of life, exposure to chemotherapy drugs leads to significant fertility problems in children with cancer. Etoposide is a chemotherapy drug that is widely used in the treatment of various types of cancer; However, it destroys healthy cells, especially male germ cells that are multiplying rapidly and continuously, and leads to infertility. In the present study, the antioxidant effect of pentoxifylline on the disorder caused by etoposide on the sperm parameters of adult male NMRI mice was investigated. Materials and methods: 24 adult male NMRI mice with an average weight of 35±2gr (n=6) were randomly allocated to the following groups (n=6): control, etoposide (1mg/kg), pentoxifylline (100mg/kg) and etoposide + pentoxifylline and treated with daily intraperitoneal injection for 35 days. At the end of the treatment period, mice were anesthetized with ketamine-xylazine solution, and the left caudal region of epididymis was transferred to a 3cm plate containing culture medium (HamsF10) in a 37°C incubator to examine sperm parameters including the number, motility, morphology, viability and tail length of the sperm. The denaturation of sperm DNA using acridine orange staining and the maturation rate of sperm nucleus using aniline blue staining method was measured. The left testicle was removed and used to calculate daily sperm production. After taking blood from the heart and preparing serum, total antioxidant capacity,and malondialdehyde level were also measured. The data were statistically analyzed with SPSS software, one-way ANOVA, and Tukey's test, and the difference in means was considered significant at the P<0.05 level. Results: A significant decrease in the mean percentage of progressive sperms and a significant increase in the mean percentage of in situ and immotile sperms were observed in the etoposide group compared to the control group (P<0.001). Also, a significant decrease in the mean count, viability, daily sperm production, tail length, and normal morphology of sperm was observed in the etoposide group compared to the control group (P<0.001). The total antioxidant capacity also decreased significantly in the etoposide group compared to the control group (P<0.001). The level of serum malondialdehyde showed a significant increase in the etoposide group compared to the control group (P<0.001). There was no significant difference in the mean percentage of sperm DNA damage and sperm nucleus maturation in the etoposide group compared to the control group (P<0.05). Simultaneous treatment of pentoxifylline with etoposide significantly improved the aforementioned parameters compared to the etoposide group. Conclusion: The results in the etoposide treatment group showed a significant decrease in sperm parameters and total antioxidant capacity, as well as a significant increase in malondialdehyde levels. The toxicity induced by etoposide through the induction of apoptosis, oxidative stress, and lipid peroxidation is considered the primary cause of the resulting damage, as evidenced by the study results. Pentoxifylline is believed to have mitigated the harmful effects of etoposide on sperm parameters and oxidative stress by leveraging its antioxidant properties to reduce oxidative stress. [ABSTRACT FROM AUTHOR]

Summary There is an urgent need for an oral, efficient and safe regimen for high‐risk APL under the pandemic of COVID‐19. We retrospectively analysed 60 high‐risk APL patients. For induction therapy (IT), in addition to all‐trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650–1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8–44) versus 35 days (32–42; p = 0.75) and 3 months (0.8–3.5) versus 3.3 months (2.4–3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2‐year estimated overall survival and event‐free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high‐risk APL. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the "classical" protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide-resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage-independent growth of etoposide-resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide-resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide-resistant RB cells. These impacts mirror PTPRE KD effects, indicating a regulation of PTPRE via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and—dependent on the cell line—AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma. [ABSTRACT FROM AUTHOR]

Background: Consolidative thoracic radiotherapy (cTRT) has previously shown benefit to patients with extensive stage small cell lung cancer (ES‐SCLC) who respond to chemotherapy. However, the optimum dose of cTRT is unknown. The purpose of this randomized trial is to compare the efficacy of 45 Gy in 15 fractions with 30 Gy in 10 fractions cTRT in ES‐SCLC. Methods: This phase III, multicenter, randomized trial is designed to evaluate the safety and efficacy of different cTRT dose in ES‐SCLC. Eligible patients with pathologically confirmed ES‐SCLC who responded to 4–6 cycles of etoposide plus cisplatin (EP) or carboplatin (EC) chemotherapy were randomized 1:1 to receive either 30 Gy in 10 fractions (standard dose) or 45 Gy in 15 fractions (high dose) cTRT. The primary endpoint is 2‐year overall survival (OS). Secondary endpoints include 2‐year progression‐free survival (PFS), 2‐year local control (LC) and treatment related toxicity as measured by adverse events according to the Common Terminology Criteria for Adverse Events (version 4.0). Discussion: The present study is the first randomized phase III trial designed to evaluate the efficacy of higher versus lower dose cTRT in ES‐SCLC, providing evidence for future clinical practice in prolonging survival of patients with ES‐SCLC. [ABSTRACT FROM AUTHOR]

Objectives: The recommended treatment for limited‐stage small‐cell lung cancer (LS‐SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4–6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS‐SCLC who received either 6 cycles or 4–5 cycles of EP chemotherapy combined with TRT. Materials and Methods: In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS‐SCLC patients who received 4–6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4–5 cycles. To assess overall survival (OS) and progression‐free survival (PFS), we employed the Kaplan–Meier method after conducting propensity score matching (PSM). Results: Among the 265 LS‐SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4–5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4–5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6–53.1 months) vs. 22.7 months (95% CI, 20.8–29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7–30.5 months) vs. 12.0 months (95% CI, 9.8–14.2 months), respectively, p = 0.006]. The two‐year and five‐year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4–5 cycles group, respectively. Conclusion: Patients diagnosed with LS‐SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4–5 cycles. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic neuroendocrine tumors are a rare and heterogenous group of neoplasms. Surgical resection is the only curative option. However, there has been an increase in palliative medical options. The aim of this retrospective study was to investigate responses for the most commonly used medical treatments in 192 patients. The current results support the effectiveness of somatostatin analogues in low-grade tumors and showed that it might also be used in patients with Ki-67 ≥ 10%. Treatment with streptozocin and 5-floururacil as first-line treatment showed good efficacy for G2 disease. Due to good efficacy and generally good tolerability PRRT might be considered as first-line treatment for NET G2. The results confirmed poor prognosis in high-grade tumors treated with carboplatin/etoposide or temozolomide. The current results provide valuable knowledge as current treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Background: Given the rarity and heterogeneity of pancreatic neuroendocrine neoplasms (pNEN), treatment algorithms and sequencing are primarily guided by expert opinions with limited evidence. Aim: To investigate overall survival (OS), median progression-free survival (mPFS), and prognostic factors associated with the most common medical treatments for pNEN. Methods: Retrospective single-center study encompassing patients diagnosed and monitored between 2000 and 2020 (n = 192). Results: Median OS was 36 (95% CI: 26–46) months (99 months for grade (G) 1, 62 for G2, 14 for G3, and 10 for neuroendocrine carcinomas). Patients treated with somatostatin analogues (SSA) (n = 59, median Ki-67 9%) had an mPFS of 28 months. Treatment line (HR (first line as reference) 4.1, 95% CI: 1.9–9.1, p ≤ 0.001) emerged as an independent risk factor for time to progression. Patients with a Ki-67 index ≥10% (n = 28) had an mPFS of 27 months. Patients treated with streptozocin/5-fluorouracil (STZ/5FU) (n = 70, first-line treatment n = 68, median Ki-67 10%) had an mPFS of 20 months, with WHO grade serving as an independent risk factor (HR (G1 (n = 8) vs. G2 (n = 57)) 2.8, 95% CI: 1.1–7.2, p-value = 0.031). Median PFS was 21 months for peptide receptor radionuclide therapy (PRRT) (n = 41, first line n = 2, second line n = 29, median Ki-67 8%), 5 months for carboplatin and etoposide (n = 66, first-line treatment n = 60, median Ki-67 80%), and 3 months for temozolomide-based therapy (n = 56, first-line treatment n = 17, median Ki-67 30%). Conclusion: (1) Overall survival was, as expected, highly dependent on grade; (2) median PFS for SSA was around 2.5 years without difference between tumors with Ki-67 above or below 10%; (3) STZ/5FU as first-line treatment exhibited a superior mPFS of 20 months compared to what has historically been reported for targeted treatments; (4) PRRT in G2 pNEN achieved an mPFS similar to first-line chemotherapy; and (5) limited treatment efficacy was observed in high-grade tumors when treated with carboplatin and etoposide or temozolomide. [ABSTRACT FROM AUTHOR]

Monitoring etoposide is important due to its wide usage in anti-tumor therapy; however, the commonly used HPLC method is expensive and often requires complicated extraction and detection procedures. Electrochemical analysis has great application prospects because of its rapid response and high specificity, sensitivity, and efficiency with low cost and high convenience. In this study, we constructed a nanoporous gold (NPG)-modified GCE for the detection of etoposide. The electrochemical oxidation of etoposide by NPG caused a sensitive current peak at +0.27 V with good reproductivity in 50 mM of phosphate buffer (pH 7.4). The relationship between etoposide concentration and peak current was linear in the range between 0.1 and 20 μM and between 20 and 150 μM, with a detection sensitivity of 681.8 μA mM−1 cm−2 and 197.2 μA mM−1 cm−2, respectively, and a limit of detection (LOD) reaching 20 nM. The electrode had a good anti-interference ability to several common anions and cations. Spiked recovery tests in serum, urine, and fermentation broth verified the excellent performance of the sensor in terms of sensitivity, reproducibility, and specificity. This may provide a promising tool for the detection of etoposide in biological samples. [ABSTRACT FROM AUTHOR]

In childhood, retinoblastoma (RB) is the most common primary tumor in the eye. Long term therapeutic management with etoposide of this life-threatening condition may have diminishing effectiveness since RB cells can develop cytostatic resistance to this drug. To determine whether changes in receptor-mediated control of Ca2+ signaling are associated with resistance development, fluorescence calcium imaging, semi-quantitative RT-qPCR analyses, and trypan blue dye exclusion staining patterns are compared in WERI-ETOR (etoposide-insensitive) and WERI-Rb1 (etoposide-sensitive) cells. The cannabinoid receptor agonist 1 (CNR1) WIN55,212-2 (40 µM), or the transient receptor potential melastatin 8 (TRPM8) agonist icilin (40 µM) elicit similar large Ca2+ transients in both cell line types. On the other hand, NGF (100 ng/mL) induces larger rises in WERI-ETOR cells than in WERI-Rb1 cells, and its lethality is larger in WERI-Rb1 cells than in WERI-ETOR cells. NGF and WIN55,212-2 induced additive Ca2+ transients in both cell types. However, following pretreatment with both NGF and WIN55,212-2, TRPM8 gene expression declines and icilin-induced Ca2+ transients are completely blocked only in WERI-ETOR cells. Furthermore, CNR1 gene expression levels are larger in WERI-ETOR cells than those in WERI-Rb1 cells. Therefore, the development of etoposide insensitivity may be associated with rises in CNR1 gene expression, which in turn suppress TRPM8 gene expression through crosstalk. [ABSTRACT FROM AUTHOR]

Objectives To assess if the distribution of villous intraepithelial lymphocytes (IELs) in a pediatric cohort with Marsh I histopathology is specific to celiac disease (CeD). Methods Multicenter, retrospective case-control study between January 2001 and December 2019 in children (<18 years) with and without CeD with intraepithelial lymphocytosis and normal villous architecture. Pathology specimens were reviewed by 2 study pathologists who were blinded to the final diagnosis. Morphologic features (villous height to crypt depth ratio [Vh:Cd]) and IELs in the villous tip, top, or bottom half of the villus were quantified. Results Of the 97 children with Marsh I histopathology identified during the study period, 63 were excluded due to an insufficient number of well-oriented villous-crypt complexes or a Vh:Cd less than 2. Villous IELs were measured in 34 cases (14 CeD, 20 non-CeD controls). There was no difference between the non-CeD and CeD groups in the mean IELs at the villous tip (14.0 ± 7.1 vs 11.7 ± 6.0, P =.31), top (46.4 ± 18.4 vs 38.3 ± 10.8, P =.11), or bottom (29.8 ± 16.8 vs 28.5 ± 12.8, P =.80) half of each villus, respectively. Conclusions The distribution of IELs in Marsh I lesions is not specific for CeD. [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]

Aim: The aim of this study was to investigate the responses of antiapoptotic Bcl-2 and proapoptotic Bid genes to Mitotane and other chemotherapy drugs in Adrenocortical Carcinoma (ACC) cells. The purpose was to understand the effects of these chemotherapy drugs on apoptosis-related genes in ACC and to identify potential treatment pathways. Materials and Methods: The study involved the use of ACC cells to assess gene expressions in response to treatment with Mitotane, Etoposide, and Cisplatin. Gene expression levels of Bcl-2 and Bid were measured after drug exposure, providing insight into the modulation of apoptosis pathways by Rt-qPCR. Results: The results demonstrated that Mitotane notably affected the expression of the proapoptotic Bid gene in ACC cells, promoting apoptosis. Cisplatin increased the expression of the antiapoptotic Bcl-2 gene and decreased the expression of the proapoptotic Bid gene compared to Mitotane. Conclusion: This study showed that Mitotane, like other chemotherapy drugs, affects the expression of key apoptosis-related genes in ACC cells. Mitotane significantly affected the proapoptotic Bid gene, indicating its potential as a treatment option for ACC. These findings suggest that Mitotane affects ACC cells, highlighting its importance in ACC therapy. [ABSTRACT FROM AUTHOR]

The article describes the case of a 14-year-old female with a history of rapidly growing right cheek mass and was diagnosed of adamantinoma-like Ewing sarcoma (ALES). Topics discussed include clinical characteristics of Ewing sarcoma (ES), the discovery of other soft tissue tumors that share a translocation between the EWSR1 gene and the ETS gene family, and treatment for most pediatric parotid tumors.

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]

Simple Summary: Chemotherapy using carboplatin and etoposide (CE) is often proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) and adenocarcinoma. We aimed to investigate the benefit of CE, especially in patients with heavily pretreated adenocarcinoma. In this retrospective series, we showed that the reports of clinical results of CE indicate that we should not mix PSC-NE and adenocarcinoma. In patients with PSC-NE, 58.8% had a radiological response to CE and median progression-free survival was 7.9 months. In pretreated patients with adenocarcinoma, the benefit/risk ratio of CE seems unfavorable with poor response and high toxicity irrespective of the elevation of neuroendocrine markers. Background: Chemotherapy using carboplatin and etoposide (CE) is frequently pragmatically proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) carcinoma and adenocarcinoma with or without neuroendocrine (NE) marker elevation. However, the real benefit of CE is poorly reported in the recent therapeutic context. Methods: We retrospectively analyzed the efficacy and tolerance of CE chemotherapy in these three different groups of mPC patients. Efficacy endpoints included radiological response, progression-free survival (PFS), and overall survival (OS), as well as PSA response and PFS2/PFS1 ratio in patients with adenocarcinoma. Results: Sixty-nine patients were included in this single-center study (N = 18 with PSC-NE carcinoma and 51 with adenocarcinoma with (N = 18) or without (N = 33) NE marker elevation). Patients with adenocarcinoma were highly pretreated with next-generation hormonal agents (NHAs) and taxanes. In patients with adenocarcinoma, a PSA response ≥50% was observed in six patients (15.8%), four of whom had NE marker elevation. The radiological response was higher in PSC-NE and tended to be higher in adenocarcinoma when NE marker elevation was present. Comparing patients with adenocarcinoma with vs. without NE marker elevation, the median PFS was 3.7 and 2.1 months and the median OS was 7.7 and 4.7 months, respectively. Overall, 62.3% of patients experienced grade 3–4 adverse events (mainly hematological), and three treatment-related deaths were recorded. Conclusion: Reports of the clinical results of CE suggest that we should not mix PSC-NE and castration-resistant adenocarcinoma of the prostate. In patients with heavily pretreated adenocarcinoma, the benefit/risk ratio of CE chemotherapy seems unfavorable due to poor response and high toxicity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Etoposide induces oxidative stress in P. aeruginosa. • Etoposide induces emergence of ciprofloxacin-resistant Pseudomonas aeruginosa. • Etoposide-treated Ciprofloxacin-resistant P. aeruginosa possess gyrase mutations. • Microfluidics-based lung tumor-bacteria model reveals survival against Etoposide. • Etoposide-evolved bacterial biofilms protect tumor cells from Etoposide killing. • Etoposide-evolved bacterial biofilms promote tumor progression. Antibiotic-resistant bacterial infections, such as Pseudomonas aeruginosa and Staphylococcus aureus, are prevalent in lung cancer patients, resulting in poor clinical outcomes and high mortality. Etoposide (ETO) is an FDA-approved chemotherapy drug that kills cancer cells by damaging DNA through oxidative stress. However, it is unclear if ETO can cause unintentional side effects on tumor-associated microbial pathogens, such as inducing antibiotic resistance. We aimed to show that prolonged ETO treatment could unintendedly confer fluoroquinolone antibiotic resistance to P. aeruginosa , and evaluate the effect of tumor-associated P. aeruginosa on tumor progression. We employed experimental evolution assay to treat P. aeruginosa with prolonged ETO exposure, evaluated the ciprofloxacin resistance, and elucidated the gene mutations by DNA sequencing. We also established a lung tumor- P. aeruginosa bacterial model to study the role of ETO-evolved intra-tumoral bacteria in tumor progression using immunostaining and confocal microscopy. ETO could generate oxidative stress and lead to gene mutations in P. aeruginosa , especially the gyrase (gyrA) gene, resulting in acquired fluoroquinolone resistance. We further demonstrated using a microfluidic-based lung tumor- P. aeruginosa coculture model that bacteria can evolve ciprofloxacin (CIP) resistance in a tumor microenvironment. Moreover, ETO-induced CIP-resistant (EICR) mutants could form multicellular biofilms which protected tumor cells from ETO killing and enabled tumor progression. Overall, our preclinical proof-of-concept provides insights into how anti-cancer chemotherapy could inadvertently allow tumor-associated bacteria to acquire antibiotic resistance mutations and shed new light on the development of novel anti-cancer treatments based on anti-bacterial strategies. [ABSTRACT FROM AUTHOR]

Nilutamide (1) of the NO2 group can be converted to NH2 by addition of triethyl silane and Wilkinson's catalyst to give amino compound (2) via reduction. It is further treated with t_BuONO by TMSN3 in RB flask containing CH3CN to give 3-(4-(4-azido-3-(trifluoromethyl) phenyl)-5-5-dimmethylimidazolidine-2,4-dione (3). Azide furthermore reacted with different terminal alkynes in the presence of Sharpless catalyst to form 5,5-dimethyl-3-(4-(4-phenyl-1H-1,2,3-triazol-1-yl)-3-trifluoromethyl imidazolidine-2,4-diones(4a-4j) with favorable yields depicted (scheme-I) in this manuscript. All the compounds were screened for in vitro anti-cancer activity, among them compound 4h containing the 4-CN group showed highest anticancer activity PC3=-1.94±1.16µM and DU-145=1.54±0.32 and MCF-7=1.43±0.92 µM. Compound 4d NO2 group resulting compound 4d exhibited PC3 3.38±2.07 and DU-145 =3.58±1.57 µM. Compound 4C containing Ome group PC3=2.10±1.38, DU-145=1.57±0.32 and MCF-7=2.08±1.64 µM as IC50 in µM, Etoposide is used as a reference. [ABSTRACT FROM AUTHOR]

Transformed small cell lung cancer (T-SCLC) is a highly aggressive clinical disease with a notably poor prognosis. It most often arises from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) following treatment. To date, no standard treatment has been established for T-SCLC. Platinum-etoposide was the most commonly used regimen, but progression-free survival remains unsatisfactory. Therefore, there is an urgent unmet need to develop novel and effective strategies for this population. Our study, a multicentre, open-label, single-arm phase II clinical trial (NCT05957510), aims to evaluate the efficacy and safety of serplulimab plus chemotherapy in untreated T-SCLC patients after histological transformation. In total, 36 eligible participants experiencing SCLC transformation from EGFR -mutant NSCLC will be enrolled to receive combination therapy of serplulimab, etoposide and carboplatin for four to six cycles, followed by maintenance therapy with serplulimab for up to 2 years. The primary endpoint is progression-free survival; secondary endpoints include objective response rate, overall survival and safety. Enrolment started in July 2023 and is ongoing, with an estimated completion date of December 2025. This study aims to provide valuable insights into the efficacy and safety of combining serplulimab with chemotherapy for treating patients with T-SCLC originating from EGFR -mutant NSCLC. • T-SCLC is a highly aggressive disease with a poor prognosis and lacks standard treatment. • Adding immunotherapy to chemotherapy might improve outcomes for T-SCLC but lacks clinical evidence. • The first prospective trial to investigate the efficacy of serplulimab plus chemotherapy for T-SCLC. • The exploratory analysis aims to identify potential biomarkers for immunotherapy in T-SCLC. [ABSTRACT FROM AUTHOR]

Introduction: Etoposide is a key component of many pediatric chemotherapy regimens for both hematologic and solid tumors. It is well documented that patients receiving etoposide may experience infusion-related reactions. Methods: In this study, total doses of etoposide and etoposide phosphate were identified, and infusion-related reactions were retrospectively evaluated at a large pediatric oncology ambulatory clinic. The primary outcome was to determine the rate of acute infusion-related reactions to etoposide. A secondary objective was to identify potential risk factors associated with such reactions. Results: Overall, 1463 doses of etoposide were dispensed to 150 unique patients and 15 patients (10%) experienced etoposide infusion-related reactions. Of the 15 patients that experienced etoposide infusion-related reaction, two were successfully able to tolerate subsequent infusions with a slower etoposide infusion rate and pre-medications. The remaining patients changed drug formulation to etoposide phosphate (n = 12) or continued therapy without any formulation of etoposide (n = 1). Patients with classical Hodgkin's lymphoma experienced a higher incidence of infusion-related reactions compared to the overall patient population (30.5% vs. 10%) and made up 73.3% of all infusion-related reactions during the study period. Conclusions: During the examined study period, 10% of patients experienced an acute infusion-related reaction to etoposide. This review builds on previous literature concluding that additional monitoring may be warranted in patients with classical Hodgkin's lymphoma receiving etoposide. [ABSTRACT FROM AUTHOR]

Introduction: Antineoplastic drugs (ADs) are commonly used pharmaceuticals for anticancer treatments. It has previously been shown that the external surface of drug vials frequently is contaminated with ADs. More than a decade ago methods to prevent occupational exposure were introduced by using plastic coverage of the glass vials or packing vials in a secondary plastic container. The aim of the pilot study was to determine contamination levels of ADs on different parts of AD packaging of two different commercially available drug vials on the Swedish market and to investigate the occurrence of cross contamination of ADs. Methods: Packagings of gemcitabine (GEM) and 5-fluorouracil (5-FU) were tested by wipe sampling. Five ADs; GEM, 5-FU, cyclophosphamide (CP), ifosfamide and etoposide were quantified using liquid chromatography mass spectrometry. Results: AD contaminations were detected in 69% and 60% of the GEM and 5-FU packaging samples. Highest levels, up to approximately 5 µ g/sample, were observed on the glass vials. The protective shrink-wrap of 5-FU vials and the plastic container of GEM were contaminated with low levels of 5-FU and GEM, respectively, and furthermore the 5-FU vials with shrink-wrap were cross-contaminated with GEM. Cross-contamination of CP and GEM was detected on 5-FU vials with plastic shrink-wrap removed. Conclusions: External contamination of ADs are still present at primary drug packagings on the Swedish market. Protection of AD vials by plastic shrink-wrap or a secondary plastic container does not remove the external contamination levels completely. The presence of cross contamination of ADs on drug packagings was also observed. [ABSTRACT FROM AUTHOR]

Background: Recurrent high-grade glioma patients exhibited poor survival. Chemotherapy such as cisplatin and Etoposide may overcome tumor cell resistance. Multiple phases I and II trials have revealed the safety and efficacy of Temozolomide (TMZ) combined with interferon, nitrosoureas, bevacizumab and other chemotherapeutic agents such as irinotecan, pegylated doxorubicin and cisplatin given in progressive as well as recurrent glioblastoma multiforme (GBM). We aimed to evaluate the impact of cisplatin plus TMZ versus Carboplatin plus Etoposide in treating recurrent high-grade glioma on clinical outcomes. Methods: 40 patients were enrolled in this study, where 25 patients diagnosed with recurrent high-grade glioma received cisplatin plus TMZ versus, the other 15 patients received Carboplatin and Etoposide to evaluate toxicity and survival in both groups. Results: Both studied arms have shown tolerable toxicity findings with no statistical difference. Progression was observed more in patients who received Carboplatin + Etoposide protocol than cisplatin + TMZ. However, of no statistical significance (P = 0.44), the median PFS of both arms were 5 ± 0.63 and 7 ± 1.87 months, median OS was 9 ± 1.54, and 11 ± 1.66 months, respectively, without any significant difference. Conclusions: Cisplatin plus TMZ combination had shown an accepted toxicity profile and survival outcome in terms of PFS and OS compared to Carboplatin plus Etoposide protocol without significance. MGMT, EGFR, and PI3K molecular studies could promise survival gains. [ABSTRACT FROM AUTHOR]

The patient in this report was a 73‐year‐old male who was diagnosed with small cell lung cancer (T3N0M0 stage IIB) after presenting with a 5.5 cm tumor detected in the right lower lobe of the lung by radiography. After right lower lobectomy and lymphadenectomy, postoperative adjuvant chemotherapy was administered with cisplatin and etoposide. At 27 months after surgery, the patient complained of wheezing. Tracheal metastasis was identified through computed tomography and bronchoscopy. Biopsy confirmed metastasis of small cell lung cancer. Radiotherapy (60 Gy) was administered to the mediastinal lymph nodes, including the supraclavicular region. The patient then underwent four cycles of carboplatin‐etoposide‐durvalumab, followed by durvalumab maintenance therapy. At 49 months after surgery, the patient complained of discomfort while speaking, leading to the discovery of a nodule in the subglottic space, which confirmed small cell lung cancer metastasis. Radiotherapy (30 Gy) was administered to the larynx and mediastinum, and the patient continued with durvalumab monotherapy. As of 61 months after surgery, he remains recurrence‐free after the second course of radiotherapy. Our favorable outcome could be explained by the synergy between immunotherapy and radiotherapy. Here, we report a rare case of postoperative tracheal metastasis in small cell lung cancer successfully managed with radiotherapy and durvalumab. This shows promise in achieving local disease control and extending survival in postoperative metastatic lesions, highlighting a potential therapeutic approach. [ABSTRACT FROM AUTHOR]

Selinexor, an oral inhibitor of the nuclear transport protein Exportin-1, shows promising single-agent activity in clinical trials of relapsed/refractory (R/R) acute myeloid leukemia (AML) and preclinical synergy with topoisomerase (topo) IIα inhibitors. We conducted a phase 1, dose-escalation study of selinexor with mitoxantrone, etoposide, and cytarabine (MEC) in 23 patients aged < 60 years with R/R AML. Due to dose-limiting hyponatremia in 2 patients on dose level 2 (selinexor 40 mg/m2), the maximum tolerated dose was 30 mg/m2. The most common grade ≥ 3 treatment-related non-hematologic toxicities were febrile neutropenia, catheter-related infections, diarrhea, hyponatremia, and sepsis. The overall response rate was 43% with 6 patients (26%) achieving complete remission (CR), 2 (9%) with CR with incomplete count recovery, and 2 (9%) with a morphologic leukemia-free state. Seven of 10 responders proceeded to allogeneic stem cell transplantation. The combination of selinexor with MEC is a feasibile treatment option for patients with R/R AML. [ABSTRACT FROM AUTHOR]

The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell transplantation (ASCT) is a commonly used intensification regimen for patients with Hodgkin lymphoma. As etoposide and cytarabine dosing are not defined, we conducted a retrospective, multicenter study, to compare efficacy and toxicity in 130 patients with Hodgkin lymphoma receiving etoposide and cytarabine at either 200 mg/m2/d (n = 50), 400 mg/m2/d (n = 35), or etoposide 200 mg/m2/d and cytarabine 400 mg/m2/d (n = 45). Progression-free survival and overall survival were not associated with the intensity of conditioning. Increased conditioning intensity was associated with longer duration of thrombocytopenia, a higher number of transfused RBC and platelet units and a higher frequency of mucositis, but serious adverse events or infectious complications were not increased. The intensity of BEAM regimen was not associated with survival but with the rate of cytopenia and mucositis advocating for the use of lower dosing in frail patients. [ABSTRACT FROM AUTHOR]

AbstractThis work aims to comprehend the physicochemical interaction of etoposide (trade name “VP-16”) with biological membranes using biomembrane models. Surfactants, owing to their remarkable chemical similarity with biomembranes, can be used to simulate the interactions and behavior of VP-16 in biological systems. The present study explores the physicochemical interactions of chemopreventive VP-16 with ionic dodecyltrimethylammonium bromide (DTAB), sodium dodecyl sulfate (SDS), and nonionic TX-100 & Tween-80 surfactants at the molecular level using different techniques. UV-visible spectroscopy results at 298.15 K indicate that both hydrophilic and hydrophobic interactions significantly influence the solubility of the drug in micellar systems. According to the estimated partition coefficient (Kx) and binding constant (Kb) obtained from the differential mode of the UV-Vis, VP-16 exhibits better binding and partitioning with nonionic surfactants compared to ionic surfactants. Thermodynamic parameters (ΔHmo, ΔSmo, & ΔGmo) are computed from 298.15 K to 318.15 K with a temperature interval of 5 K using conductivity data. The positive values of ΔHmo and ΔSmo and the negative values of ΔGmo indicate the disruption of water structure during the micellization process in the presence of VP-16 and the spontaneous transport of drug molecules into micelles, respectively. Voltammetric data at 298.15 K show that DTAB and TX-100 favor the oxidation of VP-16. This kind of study may be used to modify currently available drugs, design new chemotherapeutics, and formulate effective drug delivery systems to boost the drugs bioavailability. [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]

• The extract from Juniperus drupacea had a cytotoxic effect on glioblastoma cells. • The molasses from Juniperus drupacea had a cytotoxic effect on glioblastoma cells. • The molasses from Juniperus drupacea was more cytotoxic than its extract. • Juniperus drupacea may have the potential as a therapeutic for glioblastoma. Glioblastoma (GBM) is a prevalent and most malignant kind of glioma, reported as grade IV glioma by the World Health Organization. In a year 3–10 per 100.000 people are diagnosed with GBM and their mean life expectancy could only be 12–16 months after diagnosis. Juniperus drupacea, a member of the Cupressaceae family is a medicinal herb. In this study, the free radical scavenging activity and volatile components of Juniperus drupacea were analyzed and the cytotoxic effects of Juniperus drupacea molasses and cone seed extract in combination with etoposide on GBM cell line (U-87 MG (ATCC® HTB-14TM)) were evaluated. Furthermore, the impact of Juniperus drupacea extract on the migration capacity of GBM cells was examined. Based on the DPPH radical scavenging activity assay, the amount of free radical-binding antioxidants in the Juniperus drupacea extract was found to be 0.575 mg/mL Trolox equivalent. The results of the cytotoxicity and migration assays revealed that Juniperus drupacea reduced the viability and migration capacity of GBM cells and increase the cytotoxic effect of etoposide. Considering these findings, it was hypothesized that some of the components of Juniperus drupacea might have possible therapeutic effects for the treatment of glioblastoma. [ABSTRACT FROM AUTHOR]

The article focuses on a randomized phase III trial comparing first-line platinum-based treatments for extended stage small cell lung cancer. Topics include the historical treatment approach, the trial methodology comparing topotecan/cisplatin with etoposide/carboplatin, and the final results indicating no significant difference in overall survival or progression-free survival between the treatments, despite variations in hematological toxicity.

Medium-dose etoposide (ETP), cyclophosphamide (CY) and total body irradiation (TBI) is a beneficial conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in adults with acute lymphoblastic leukemia (ALL), especially with high-risk ALL, as compared with CY and TBI conditioning. ETP may enhance immunogenicity of leukemia-associated antigens through increased expression of major histocompatibility antigen complex class I, leading to cross-priming of T cells by dendritic cells and generating leukemia-specific cytotoxic T cells. Furthermore, ETP can eliminate activated effector T cells, sparing naïve and memory T cells, accompanied with depletion of regulatory T cells. These mechanisms are supposed to lead to inhibit immune escape of leukemia cells and enhance anti-leukemia immunity in addition to direct cytotoxicity of ETP, followed by an efficient eradication of leukemia cells. According to the findings of pharmacokinetics studies, spreading the administration of low-dose ETP may be more efficacious than non-spreading administration, to induce a potent anti-leukemia immunity without aggravating graft-versus-host disease and transplant-related toxicity. In the present review, I discuss the immunological aspects elicited by the addition of medium-dose ETP to the CY/TBI conditioning and the possible positioning of allo-HCT with this conditioning in adults with ALL, considering recent progress in non-HCT treatment including bispecific antibody-based therapy. [ABSTRACT FROM AUTHOR]

Background: Hepatocellularcarcinoma(HCC)isthe most common type of liver cancer worldwide. The current remedies for cancer, including chemotherapy and radiation therapy, might damage patients' organs, sometimes causing death. Etoposide (ETO), as a widely used chemo-drug, possesses the same problems. For years, combinational therapy has been considered a potential adjustor for common treatments, alleviating their side effects. Quercetin (Que), a phytochemical drug, has been used due to its potential against cancer. Objectives: This study explored whether synergy occurs between Que and ETO on the apoptosis of HepG2 HCC cells or not. Methods: The impacts of the drugs on cell growth were assessed through the MTT assay. The apoptotic death rates of treated cells were examined through Annexin/PI double staining and caspase-9 and caspase-3 activities. The relative expression of B-cell lymphoma 2 (Bcl-2) associated X-protein (Bax), and Bcl-2 genes and proteins were analyzed using quantitative reverse transcription polymerase chain reaction and western blot analysis. Additionally, the levels of p53 protein were determined. Results: Both Que and ETO reduced the cell viability and increased apoptotic rates, caspases activities, Baxgene and protein expression, and the p53 protein levels of HepG2 cells. The combination of Que and ETO showed apparent synergy in terms of cell growth and cell apoptosis. Que significantly enhanced the effects of ETO on caspase activities, Bax and Bcl-2 genes' expression, and p53 protein levels. Conclusions: The obtained results demonstrated that Que showed synergy when co-treated with ETO on HepG2 cells. Therefore, it is concluded that further studies on the aforementioned combination could lead to a potential anticancer compound against HCC. [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]

Simple Summary: Lung cancer, responsible for nearly 20% of global cancer-related deaths annually, is the leading cause of cancer mortality. Traditional treatments, like chemotherapy and radiation, are not always effective or appropriate due to the heterogeneity of lung cancer across patients. To address this challenge, our research introduces an approach to develop patient-derived spheroids (PDS) that are cultivated using cells from patient tumors and adjacent healthy tissue. These PDS allow us to mimic the unique microenvironment of patients, introducing a platform to assess personalized responses to drug treatments. We used this system to characterize patient cell populations, evaluate gene expression, and assess the sensitivity of PDS to specific drugs. By introducing a patient-specific platform to test drug sensitivity, our study holds the potential to enhance the efficacy of lung cancer treatments, paving the way for individualized and more effective lung cancer therapies in the future. Lung cancer is the leading cause of cancer mortality worldwide, with a median survival rate at 5 years of less than 20%. While molecular mapping aids in selecting appropriate therapies, it cannot predict personalized treatment response and long-term efficacy. For addressing these challenges, there is a great need for functional tests. Within this context, we developed patient-derived spheroids (PDS) from tumor and adjacent normal tissue to biomimic the respective tissue for assessing the personalized drug treatment response in vitro. Surgically resected lung specimens were used to generate spheroids using a two-step culture procedure. Flow cytometry and immune staining enabled the characterization of different cell populations resulting from the lung samples. PDS phenotype, cell proliferation and apoptosis were evaluated. Differential gene expression between tumor and adjacent normal tissue was analyzed via RT-qPCR. PDS drug sensitivity was assessed using a cell metabolic assay in response to two chemotherapeutic drug combinations. Cellular and molecular analysis revealed the proportion of epithelial cells, fibroblasts, and immune cells in the patients' tissue samples. Subsequently, PDS models from tumor and normal lung were successfully established using the expanded epithelial cells. As a proof of concept, an analysis of the drug treatment using PDS of lung adenoid cystic carcinoma exhibited a dose-dependent effect in response to cisplatin/etoposide and cisplatin/paclitaxel. Our spheroid model of both tumor and non-tumor lung cells holds great promise for enhancing the treatment efficacy in the cancer patients. [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]

Abstract A new library of target compounds (9a-j) was designed, synthesized, and fully characterized by 1HNMR, 13CNMR, and mass spectroscopy techniques. The target compounds were screened for their cytotoxic properties against cancer cell lines Colo-205, MCF-7, A549, and A2780 by employing the MTT assay, using the etoposide as the positive control. Among the newly synthesized target compounds, four compounds 9b-9d and 9j exhibited superior cytotoxic properties to the reference standard (etoposide). In particular, compound 9b was more cytotoxic against all four cell lines with IC50 in the range of 0.016 to 0.17 μM. Further 9b is more selective toward A549 and followed by MCF-7. Molecular docking studies of all the target compounds were carried out against hDHFR to see the binding interactions and binding affinities. Ligands 9b and 9c have the highest binding affinities toward hDHFR and these results substantiate the experimental findings. The MEC was analyzed for the most potent compounds 9b and 9c. All the ligands have passed the Insilico ADME properties and haven‘t violated more than one Ro5. [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]