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Objective: To evaluate the effect of ventricular opening (VO) on recurrence patterns in patients with newly diagnosed glioblastoma (GBM) treated with bis-chloroethyl-nitrosourea (BCNU) wafer implantation. Methods: This single-center retrospective study included 40 patients with newly diagnosed GBM who received BCNU wafer implantation after tumor resection between March 2013 and February 2022. The patients were categorized into two groups based on whether VO occurred during the GBM resection. While 18 patients had VO, 22 did not have VO. In cases with VO, the ventricular wall defect is closed with gelatin or oxidized regenerated cellulose and fibrin glue before BCNU wafer implantation. Recurrence patterns—classified as local, diffuse, distant, or multifocal—and time to recurrence were compared between patients with and without VO. Results: The median follow-up period for the entire cohort was 32.2 months (interquartile range, 16.7–38 months). Median survival time was comparable between patients with VO and patients without VO (38 vs. 26 months, p=0.53). Recurrence occurred in 31/40 patients (77.5%) in entire cohort. The incidence of recurrence was comparable between patients with VO and patients without VO (14 [77.8%] vs. 17 [77.3%], p=1.0). No significant differences were seen between the two groups in time to recurrence (p=0.59) or recurrence patterns (p=0.35). Conclusion: Ventricular opening during surgery with BCNU wafer implantation does not seem to influence the recurrence patterns. Ventricular opening does not induce distant recurrence if appropriate ventricular closure is performed. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the primary cause of death from cancer in female patients. The existing treatments for ovarian cancer are restricted and ineffective in achieving a cure for the disease. To address this issue, we provide a novel approach to treating ovarian cancer by utilizing a liposomal carrier that effectively delivers the chemotherapeutic drugs carmustine (BCNU) and cabazitaxel (CTX). Initially, the combined impact of BCNU and CTX was confirmed, revealing that this impact reaches its maximum at a ratio of 1:2 mol/mol (BCNU/CTX). After that, the BC-Lipo co-delivery system was developed, which has a high capability for loading drugs (97.48% ± 1.14 for BCNU, 86.29% ± 3.03 for CTX). This system also has a sustained release profile and a beneficial long-circulating feature. The accumulation of BC-Lipo in tumors was dramatically enhanced compared to the accumulation of the free drug. Furthermore, BC-Lipo demonstrated similar levels of cytotoxicity to free BCNU and CTX (BCNU/CTX) when tested on HeyA8 cells in an in vitro model. Biochemical staining methods investigated the cancer cell's morphological examination. The apoptosis was confirmed by FITC-Annexin-V/PI staining by flow cytometry analysis. In addition, the investigation of fluorescence and protein markers examined the apoptosis mechanistic pathway, and the results indicated that BC-Lipo induced apoptosis due to mitochondrial membrane potential variation. This proof-of-concept study has established the probability of these BCNU-CTX combined treatments as active drug delivery nanocarriers for poorly soluble BCNU and CTX. [ABSTRACT FROM AUTHOR]

Background: Peripheral T‐cell lymphomas (PTCL) frequently result in relapsed or refractory diseases. Upfront autologous hematopoietic stem cell transplantation (ASCT) using the BEAM (carmustine, etoposide, cytarabine, and melphalan) regimen is recommended. However, relapses are common in PTCL, highlighting a critical need for improved survival outcomes in these patients. Objective: Anthracycline drugs are essential in treating PTCL. We compared the efficacy and tolerability of a high‐dose mitoxantrone‐based conditioning regimen [mitoxantrone, cyclophosphamide, and etoposide (MCE)] to the BEAM regimen in upfront ASCT for newly diagnosed PTCL patients who achieved complete or partial remission after induction therapy. Study Design: A retrospective study was conducted to analyze the treatment response, progression‐free survival (PFS), overall survival (OS), hematologic engraftment time, and adverse events of 64 patients between two regimens, who achieved complete or partial remission after induction chemotherapy. Twenty‐eight patients received the MCE regimen, while 36 patients were treated with the BEAM regimen. Results: There were no significant differences in clinical characteristics or the incidence of adverse events between the two groups. However, the median OS significantly favored the MCE group at 102.4 (95% CI, 87.0–117.8) months compared to 62.6 (95% CI, 50.8–74.5) months in the BEAM group (p = 0.023). Similarly, the median PFS was longer in the MCE group at 87.8 (95% CI, 65.8–109.8) months versus 42.5 (95% CI, 30.0–55.0) months in the BEAM group (p = 0.031). Conclusion: ASCT with the mitoxantrone‐based conditioning regimen is tolerable and appears to significantly improve the prognosis of PTCL patients, offering a promising alternative to the current standard of care. [ABSTRACT FROM AUTHOR]

Simple Summary: Intracavitary chemotherapy by Carmustine wafer implantation represents a therapeutic option for the management of high-grade gliomas both at diagnosis and at progression. However, this strategy is very controversial as it can lead to potential complications and previous studies have raised doubts regarding its efficacy in terms of oncological outcomes. Moreover, the results associated with Carmustine wafer implantation have been more frequently studied at diagnosis than at progression. Therefore, the aim of the present study was to precisely identify the predictors of complications and onco-functional outcomes in a series of 53 patients with a high-grade glioma surgically managed at progression with implantation of Carmustine wafers. These analyses will help to better identify and select the patients who are the best candidates to receive Carmustine wafers at progression and to guide intraoperative and postoperative management. Background/Objectives: The aim was to determine the complication rate and the predictors of complications and survival in high-grade glioma surgically managed at progression with implantation of Carmustine wafers. Methods: A retrospective series of 53 consecutive patients operated on between 2017 and 2022 was built. Results: The median age was 55 ± 10.9 years. The rates of global and infectious complications were 35.8% and 18.9%, respectively. In multivariate analysis, patients with a preoperative neurological deficit were more prone to develop a postoperative complication (HR = 5.35 95% CI 1.49–19.26, p = 0.01). No predictor of infectious complication was identified. In the grade 4 glioma subgroup (n = 44), progression-free and overall survival (calculated starting from the reresection) reached 3.95 months, 95% CI 2.92–5.21 and 11.51 months, 95% CI 9.11–17.18, respectively. Preoperative KPS > 80% (HR = 0.97 95% CI 0.93–0.99, p = 0.04), Gross Total Resection (HR = 0.38 95% CI 0.18–0.80, p = 0.01), and 3-month postoperative KPS > 80% (HR = 0.35 95% CI 0.17–0.72, p = 0.004) were predictors of prolonged overall survival. Conclusions: Surgical resection is a relevant option in high-grade gliomas at progression, especially in patients with a preoperative KPS > 80%, without preoperative neurological deficit, and amenable to complete resection. In patients elected for surgery, Carmustine wafer implantation is associated with a high rate of complications. It is consequently critical to closely monitor the patients for whom this option is chosen. [ABSTRACT FROM AUTHOR]

Drug delivery systems (DDSs) are used to transport drugs which are characterized by some pharmaceutical problems to the specific target site, enhancing therapeutic efficacy and reducing off-target accumulation in the body. In this work, one of the recently synthesized molecules, 1,10-N,N'-bis-(β-ᴅ-ureidocellobiosyl)-4,7,13,16-tetraoxa-1,10-diazacyclooctadecane (TN), was tested as a potential drug carrier towards the anticancer drug carmustine. For this purpose, different techniques were used, from synthesis and calculations to cytotoxicity assessment. Our results showed that TN is characterized by a very compact geometry, which significantly impacts its complexation properties. Although it forms a very stable complex with carmustine, it adopts a non-inclusion geometry, as verified by both experimental and theoretical NMR analyses. The cytotoxicity study performed for all analyzed molecules (TN; carmustine; TN:carmustine complex) towards normal and cancer (breast and colon) cells revealed that TN is not toxic and that the formation of complexes with carmustine reduces the toxicity of carmustine to normal cells. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas are rare heterogeneous haematological malignancies that may also involve peripheral nerves in a very small subset of cases. We report a patient with a diagnostically challenging cutaneous T-cell lymphoma and multifocal mononeuropathies in whom a targeted nerve biopsy identified lymphomatous infiltration of nerves and expedited combination treatment with chemotherapy and an autologous stem cell transplant. She showed an excellent response with a complete metabolic response on positron emission tomography imaging and significant clinical improvement, maintained 5 years post-treatment. [ABSTRACT FROM AUTHOR]

The delivery of chemotherapeutics through the blood-brain barrier remains a challenge for glioblastoma therapeutics. The overdosage of these agents also causes severe side effects among patients. Hence, there has been an urge to find alternative techniques to deliver these agents to the targeted site with limited dosage having a maximum outcome. However, when these drugs incorporated into liposomes are directed toward the tumor site, there is a higher possibility of the drugs crossing the barrier and rendering their mode of action. In our study, we aimed at formulating pH-responsive nanoliposomes loaded with carmustine that possesses selective toxicity on U87MG cells owing to the acidic pH and also evaluated their efficacy in seizing endothelial sprouting. [ABSTRACT FROM AUTHOR]

Simple Summary: This review offers a thorough examination of the potential role and structural properties of MGMT, the progression in targeting MGMT, and the interactions between MGMT and DNA repair pathways involved in processing DNA lesions. O6-methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O6-AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents such as carmustine, and thereby contributes to chemotherapeutic resistance when these agents are used. This review delves into the structural roles and repair mechanisms of MGMT, with emphasis on the potential structural and functional roles of the N-terminal domain of MGMT. It also explores the development of cancer therapeutic strategies that target MGMT. Finally, it discusses the intriguing crosstalk between MGMT and other DNA repair pathways. [ABSTRACT FROM AUTHOR]

The treatment of gliomas remains difficult task. Carmustine is a drug that is used in the treatment of gliomas. Flexible liposomes embedded in situ thermoreversible nasal gel preparations of Carmustine were studied for in vitro carmustine release, ex vivo carmustine permeation and carmustine release kinetics. The epithelial layers of nasal tissue were found to be intact and undamaged during histological analysis. Intranasal administration of optimized flexible liposomes embedded in a nasal gel showed higher Cmax (Approximately two-fold), AUC0→t (Approximately three-fold), AUC0→∞ (Approximately six-fold), and lower Tmax (1 h) in the brain, compared to intravenous injection of carmustine. The present study demonstrates that the flexible liposome embedded thermoreversible in situ intranasal gel of carmustine improved the targeted uptake of carmustine in the brain through the nasal delivery system and could be a reliable and effective delivery system for carmustine in the treatment of gliomas. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a frequent as well as violent type of brain tumor. In this research work, different carmustine formulations were prepared and screened for their cytotoxic activity against U-87 MG glioblastoma and normal human fibroblast L-929 cell lines. The flexible liposomes embedded in situ nasal gel exhibited maximum percentage of growth inhibition against U-87 MG glioblastoma cell line, and in situ nasal gel exhibited lowest percentage of growth inhibition against U-87 MG glioblastoma cell lines. Flexible liposomes embedded in situ nasal gel is observed to be safe and biocompatible against normal human fibroblast L-929 cell line. In cellular uptake study, U-87 MG cell line treated with flexible liposomes embedded in situ thermoreversible intranasal gel emitted stronger and higher intensity fluorescence. It seems that the presence of flexible liposomes embedded in situ thermoreversible nasal gel inside the tumor cells, and would be the best carmustine delivery approach for the management of GBM. [ABSTRACT FROM AUTHOR]

Carmustine (BCNU), a vital type of chloroethylnitrosourea (CENU), inhibits tumor cells growth by inducing DNA damage at O6 position of guanine and eventually forming dG-dC interstrand cross-links (ICLs). However, the clinical application of BCNU is hindered to some extent by the absence of tumor selectivity, poor stability and O6-alkylguanine-DNA alkyltransferase (AGT) mediated drug resistance. In recent years, tumor microenvironment has been widely utilized for advanced drug delivery. In the light of the features of tumor microenvironment, we constructed a multifunctional hypoxia/esterase-degradable nanomicelle with AGT inhibitory activity named HACB NPs for tumor-targeting BCNU delivery and tumor sensitization. HACB NPs was self-assembled from hyaluronic acid azobenzene AGT inhibitor conjugates, in which O6-BG analog acted as an AGT inhibitor, azobenzene acted as a hypoxia-responsive linker and carboxylate ester bond acted as both an esterase-sensitive switch and a connector with hyaluronic acid (HA). The obtained HACB NPs possessed good stability, favorable biosafety and hypoxia/esterase-responsive drug-releasing ability. BCNU-loaded HACB/BCNU NPs exhibited superior cytotoxicity and apoptosis-inducing ability toward the human uterine cervix carcinoma HeLa cells compared with traditional combined medication of BCNU plus O6-BG. In vivo studies further demonstrated that after a selective accumulation in the tumor site, the micelles could respond to hypoxic tumor tissue for rapid drug release to an effective therapeutic dosage. Thus, this multifunctional stimulus-responsive nanocarrier could be a new promising strategy to enhance the anticancer efficacy and reduce the side effects of BCNU and other CENUs. [ABSTRACT FROM AUTHOR]

The objective of the current study was to develop and optimize a novel lyophilized liposomal formulation of anticancer agent carmustine, or bis-chloroethyl nitrosourea (BCNU) for prolonged release that could overcome the dose-dependent side effects and improve its bioavailability at the site of action. The optimization was done using a 3² factorial design approach wherein soya phosphatidylcholine (SPC) and cholesterol (CH) as independent variables. The optimized formulation (F4) exhibited high entrapment efficiency (81.57%) with an average vesicle size of 141.7 nm and a -22.6 mV Zeta potential. In-vitro drug release studies from all formulations revealed that the BCNU was released for up to 36 hours following the Higuchi matrix release model. The TEM, FTIR, DSC, PXRD, and SEM analyses confirm the formation of liposomes. BCNU-loaded nanoliposomal formulation demonstrated prolonged release, suggesting that it could be used to supplement cancer therapy efficiently with a reduction in dose-dependent side effects. [ABSTRACT FROM AUTHOR]

In this research, the natural frequency behavior of functionally graded (FG) porous joined hemispherical–cylindrical–hemispherical shell vessels reinforced by graphene platelet (GPLs) has been studied for the first time. Three various types of porosity distribution are assumed through the thickness direction of shell vessel. In the two types of porosity patterns, a pattern of porosities in metal matrix is symmetric and the other one is uniform. Besides, five GPL patterns are assumed for dispersing of GPLs in metal matrix. Extended role of mixture and Tsai-Halpin is used to determine the mass density and Young's modulus of elasticity of the structure, respectively. By employing 3D elasticity theory, Hamilton's Principal and FEM in conjunction with Rayleigh–Ritz method, the governing equations of motion of the joined shell vessel are obtained and natural frequencies are extracted. The impact of various factors such as coefficient of porosity, several porosity patterns along with different GPLs distributions and weight fraction of graphene nanofillers on natural frequency behavior of FG porous joined hemispherical–cylindrical–hemispherical shell vessels reinforced by GPLs nanofillers has been reported for the first time. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to evaluate the safety and efficacy of SEAM regimen followed by auto-SCT in lymphoma. We retrospectively reviewed the records of patients with lymphoma who underwent auto-SCT with SEAM conditioning regimen from January 2010 to June 2018 at our centre. In total, 97 patients were analysed. The median time to neutrophil engraftment and platelet engraftment was 9.5 days (range, 7–15 days) and 12 days (range, 7–25 days), respectively. Grade 3–4 nausea/vomiting, mucositis and diarrhoea were observed in 21.6%, 36.1%, and 11.3% of patients, respectively. Treatment-related mortality at 100 days occurred in 2 patients (2.1%). After a median follow-up time of 53.9 months, the 3-year incidence of disease relapse or progression was 34%. The estimated progression-free survival and overall survival at 3 years were 62% and 75%, respectively. Compared with previous studies using BEAM as the conditioning regimen, this study shows that the SEAM regimen has a comparable efficacy and safety profile. The SEAM regimen is feasible and might be an ideal alternative to BEAM regimen for lymphoma auto-SCT. [ABSTRACT FROM AUTHOR]

This study aims to develop chitosan-coated PLGA nanoparticles intended for nose-to-brain delivery of carmustine. Formulations were prepared by the double emulsion solvent evaporation method and optimized by using Box-Behnken Design. The optimized nanoparticles were obtained to satisfactory levels in terms of particle size, PDI, entrapment efficiency, and drug loading. In vitro drug release and ex-vivo permeation showed sustained release and enhanced permeability (approx. 2 fold) of carmustine compared to drug suspension. The AUC 0-t of brain obtained with carmustine-loaded nanoparticles via nasal administration in Albino Wistar rats was 2.8 and 14.7 times that of intranasal carmustine suspension and intravenous carmustine, respectively. The MTT assay on U87 MG cell line showed a significant decrease (P < 0.05) in the IC50 value of the formulation (71.23 μg ml−1) as compared to drug suspension (90.02 μg ml−1).These findings suggest chitosan coated nanoparticles could be used to deliver carmustine via intranasal administration to treat Glioblastoma multiforme. [ABSTRACT FROM AUTHOR]

Gliomas are tumors of the primary central nervous system associated with poor prognosis and high mortality. The 5-year survival rate of patients with gliomas received surgery combined with chemotherapy or radiotherapy does not exceed 5%. Although temozolomide is commonly used in the treatment of gliomas, the development of resistance limits its use. MicroRNAs are non-coding RNAs involved in numerous processes of glioma cells, such as proliferation, migration and apoptosis. MicroRNAs regulate cell cycle, PI3K/AKT signal pathway, and target apoptosis-related genes (e.g., BCL6), angiogenesis-related genes (e.g., VEGF) and other related genes to suppress gliomas. Evidence illustrates that microRNAs can regulate the sensitivity of gliomas to temozolomide, cisplatin, and carmustine, thereby enhancing the efficacy of these agents. Moreover, traditional Chinese medicine (e.g., tanshinone IIA, xanthohumol, and curcumin) exert antiglioma effects by regulating the expression of microRNAs, and then microRNAs inhibit gliomas through influencing the process of tumors by targeting certain genes. In this paper, the mechanisms through which microRNAs regulate the sensitivity of gliomas to therapeutic drugs are described, and traditional Chinese medicine that can suppress gliomas through microRNAs are discussed. This review aims to provide new insights into the traditional Chinese medicine treatment of gliomas. [ABSTRACT FROM AUTHOR]

Purpose. Women with locally advanced/high-risk triple-negative breast cancer treated with the current standard chemotherapy continue to have a poor prognosis. High-dose chemotherapy with autologous stem cell transplant as treatment for locally advanced/high-risk breast cancer remains controversial due to a lack of survival benefit seen in previous phase III trials. However, these trials evaluated a heterogeneous group of patients with different receptor subtypes. A marginal benefit was observed in certain subgroups. We report long-term outcomes of women with stage IIB or III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant at our institution between 1995 and 2001. Methods. This is a retrospective analysis of stage IIB or stage III triple-negative breast cancer treated with high-dose chemotherapy followed by autologous stem cell transplant. We excluded women with hormone-positive, HER2/neu-positive/unknown, and/or metastatic disease prior to transplant as per updated AJCC 7th edition guidelines. Patients underwent surgery and either neoadjuvant or adjuvant anthracycline and taxane-based chemotherapy and then proceeded to high-dose chemotherapy and autologous stem cell transplant using carmustine 600 mg/sqm, cyclophosphamide 5.6gm/sqm, and cisplatin 165 mg/sqm (STAMP 1 regimen) for consolidation. This was followed by locoregional breast and lymph node radiation per standard of care. Results. Twenty-nine women (2 stage IIB and 27 stage III) were evaluated. The median age at diagnosis was 43 years (IQR: 40, 51). Eleven patients had 4–9 regional lymph nodes (LN) involved and 16 had 10+ involved LNs. Four patients had T4 or inflammatory breast cancer and two had ipsilateral supraclavicular LNs involved. The median follow-up time is 16 years (95% CI: 12, 19, range <1–19 y) posttransplant. The median overall survival was 15 years (95% CI: 3, 19); the median DFS was 14 years (95% CI: 1, 19). Conclusions. This study of locally advanced/high-risk triple-negative breast cancer treated with adjuvant high-dose chemotherapy and autologous stem cell transplant reveals high overall survival rate. With the current improvement in treatment-related mortality, re-evaluating this approach in this subset of high-risk breast cancer in prospective randomized studies may be worthwhile. [ABSTRACT FROM AUTHOR]

As a clinical anti-glioma agent, the therapeutic effect of carmustine (BCNU) was largely decreased because of the drug resistance mediated by O 6-alkylguanine-DNA alkyltransferase (AGT) and the blood-brain barrier (BBB). To overcome these obstacles, we synthesized a BCNU-loaded hypoxia/esterase dual stimulus-activated nanomicelle, abbreviated as T80-HACB/BCNU NPs. In this nano-system, Tween 80 acts as the functional coating on the surface of the micelle to facilitate transport across the BBB. Hyaluronic acid (HA) with active tumor-targeting capability was linked with the hypoxia-sensitive AGT inhibitors (O 6-azobenzyloxycarbonyl group) via an esterase-activated ester bond. The obtained T80-HACB/BCNU NPs had an average particle size of 232.10 ± 10.66 nm, the zeta potential of −18.13 ± 0.91 mV, and it showed high drug loading capacity, eximious biocompatibility and dual activation of hypoxia/esterase drug release behavior. The obtained T80-HACB/BCNU NPs showed enhanced cytotoxicity against hypoxic T98G and SF763 cells with IC 50 at 132.2 μM and 133.1 μM, respectively. T80 modification improved the transportation of the micelle across an in vitro BBB model. The transport rate of the T80-HACB/Cou6 NPs group was 12.37 %, which was 7.6-fold (p <0.001) higher than the micelle without T80 modification. T80-HACB/BCNU NPs will contribute to the development of novel CENUs chemotherapies with high efficacy. [ABSTRACT FROM AUTHOR]

As a clinical anti-glioma agent, the therapeutic effect of carmustine (BCNU) was largely decreased because of the drug resistance mediated by O 6-alkylguanine-DNA alkyltransferase (AGT) and the blood-brain barrier (BBB). To overcome these obstacles, we synthesized a BCNU-loaded hypoxia/esterase dual stimulus-activated nanomicelle, abbreviated as T80-HACB/BCNU NPs. In this nano-system, Tween 80 acts as the functional coating on the surface of the micelle to facilitate transport across the BBB. Hyaluronic acid (HA) with active tumor-targeting capability was linked with the hypoxia-sensitive AGT inhibitors (O 6-azobenzyloxycarbonyl group) via an esterase-activated ester bond. The obtained T80-HACB/BCNU NPs had an average particle size of 232.10 ± 10.66 nm, the zeta potential of −18.13 ± 0.91 mV, and it showed high drug loading capacity, eximious biocompatibility and dual activation of hypoxia/esterase drug release behavior. The obtained T80-HACB/BCNU NPs showed enhanced cytotoxicity against hypoxic T98G and SF763 cells with IC 50 at 132.2 μM and 133.1 μM, respectively. T80 modification improved the transportation of the micelle across an in vitro BBB model. The transport rate of the T80-HACB/Cou6 NPs group was 12.37 %, which was 7.6-fold (p <0.001) higher than the micelle without T80 modification. T80-HACB/BCNU NPs will contribute to the development of novel CENUs chemotherapies with high efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Strong interactions occur between HBC and BCNU.adsorption process and electronic. • The electronic properties of HBC are not sensitive to the presence of BCNU Detection. • The geometry of the nanographenes remains unchanged after the drug molecule. • BNHBC seems to be a suitable option for carrying and revealing BCNU drug. We conducted research on the adsorption of carmustine (BCNU) on the surface of pristine, N-doped, and BN-doped Hexa- peri -hexabenzocoronene (HBC) nanographene using density functional theory calculations. We used the B3LYP functional in conjunction with 6-31+G(d) and 6-311+G(d,p) basis sets to perform geometrical optimization calculations, vibrational frequencies, and natural bond orbitals (NBO) analysis. The dispersion correction term of Grimme-D3 was incorporated to account for the dispersion interactions. We found that the geometry of the nanographenes remains unchanged after the drug molecule adsorption. The calculated adsorption energies (E ads) were −17.1 kcal.mol−1 for HBC-BCNU, −17.0 kcal.mol−1 for NHBC-BCNU, and −17.9 kcal.mol−1 for BNHBC-BCNU when using the 6-31+G(d) basis set. The corresponding values calculated employing the 6-311+G(d,p) basis set were −17.9, −17.3, and −19.1 kcal.mol−1, respectively. Analysis of frontier molecular orbitals (HOMO and LUMO) showed that the electronic properties of NHBC were significantly affected by the presence of BCNU. We used NBO analysis to investigate the distribution of partial atomic charges in different systems. Finally, using the transition state equation and the smaller basis set, we found that the required time for BCNU to release from HBC, NHBC, and BNHBC is approximately 3.3, 1.8, and 13.0 s, respectively. The obtained values are 13.0, 4.6, and 96.0 s, respectively, for the higher level of calculations. The recovery time for all nanographenes is within a reasonable range, while NHBC exhibits the highest sensitivity for drug detection. [ABSTRACT FROM AUTHOR]

Simple Summary: Carmustine wafer (CW) implantation into the resection cavity of patients operated for glioblastoma (GBM) was approved as an adjuvant treatment before the Stupp Protocol. Although contrasting clinical results limited its use, our retrospective study on 116 GBM treated with CW showed a significant benefit in terms of OS in a subgroup of patients. Since GBM growth, progression, and drug resistance are supported by the surrounding environment, and since the tumor microenvironment (TME) is the source of druggable targets, we hypothesized that the TME of patients who benefited from CW could have different characteristics compared to patients who did not show any advantage. Exploiting a human in vitro model of glioma microenvironment and a transcriptomic approach, we found a different gene signature suggesting the importance of developing in vitro models that mimic the properties of human cancers and that can help to study individual patient characteristics at the cellular and molecular level. Despite the state-of-the-art treatment, patients diagnosed with glioblastoma (GBM) have a median overall survival (OS) of 14 months. The insertion of carmustine wafers (CWs) into the resection cavity as adjuvant treatment represents a promising option, although its use has been limited due to contrasting clinical results. Our retrospective evaluation of CW efficacy showed a significant improvement in terms of OS in a subgroup of patients. Given the crucial role of the tumor microenvironment (TME) in GBM progression and response to therapy, we hypothesized that the TME of patients who benefited from CW could have different properties compared to that of patients who did not show any advantage. Using an in vitro model of the glioma microenvironment, represented by glioma-associated-stem cells (GASC), we performed a transcriptomic analysis of GASC isolated from tumors of patients responsive and not responsive to CW to identify differentially expressed genes. We found different transcriptomic profiles, and we identified four genes, specifically down-regulated in GASC isolated from long-term survivors, correlated with clinical data deposited in the TCGA–GBM dataset. Our results highlight that studying the in vitro properties of patient-specific glioma microenvironments can help to identify molecular determinants potentially prognostic for patients treated with CW. [ABSTRACT FROM AUTHOR]

Background: Several international centres have published their experiences with outpatient autologous stem cell transplantation (ASCT) as treatment of haematological malignancies. Aim: In this single‐centre retrospective review, we aim to examine the outcomes of outpatient autograft and review healthcare resource utilisation in the pre‐cytopenic period. Methods: Patients undergoing ASCT in Royal Hobart Hospital, Tasmania between 2008 and 2018 had their records reviewed and key outcomes data collected based on whether they received inpatient/outpatient ASCT. An outpatient ASCT was defined as conditioning as an outpatient; patients could then be managed with an elective admission during the cytopenic period or admission only when clinically indicated. Results: Of 231 ASCT performed, 135 (58%) were as outpatients: 59 used carmustine‐etoposide‐cytarabine‐melphalan conditioning for lymphoma (BEAM‐ASCT) and 76 used high‐dose melphalan for myeloma and amyloidosis (MEL‐ASCT). Approximately one‐third of patients undergoing outpatient ASCT were admitted electively during nadir period; the majority of patients required minimal interventions prior to this time. The most common causes for unplanned hospitalisation (which occurred in 71 (80%) of the 89 planned outpatient transplants) were febrile neutropenia (39%) and mucositis (35%). Age was the only risk factor identified to increase risk of requiring unplanned hospitalisation. Use of oral antibiotic prophylaxis reduced febrile neutropenia rates among melphalan outpatient ASCT. Outpatient ASCT led to significantly reduced inpatient bed‐days and overall cost (approximately A$13 000–A$16 000) compared with inpatient autografts, with no significant differences in engraftment, rates of febrile neutropenia, intensive care admissions or mortality. Conclusion: Outpatient autografts may save healthcare resources without compromising patient outcomes. [ABSTRACT FROM AUTHOR]

Base excision repair (BER) removes damaged bases by generating single‐strand breaks (SSBs), gap‐filling by DNA polymerase β (POLβ), and resealing SSBs. A base‐damaging agent, methyl methanesulfonate (MMS) is widely used to study BER. BER increases cellular tolerance to MMS, anti‐cancer base‐damaging drugs, temozolomide, carmustine, and lomustine, and to clinical poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib. The poisons stabilize PARP1/SSB complexes, inhibiting access of BER factors to SSBs. PARP1 and XRCC1 collaboratively promote SSB resealing by recruiting POLβ to SSBs, but XRCC1−/− cells are much more sensitive to MMS than PARP1−/− cells. We recently report that the PARP1 loss in XRCC1−/− cells restores their MMS tolerance and conclude that XPCC1 facilitates the release of PARP1 from SSBs by maintaining its autoPARylation. We here show that the PARP1 loss in XRCC1−/− cells also restores their tolerance to the three anti‐cancer base‐damaging drugs, although they and MMS induce different sets of base damage. We reveal the synthetic lethality of the XRCC1−/− mutation, but not POLβ−/−, with olaparib and talazoparib, indicating that XRCC1 is a unique BER factor in suppressing toxic PARP1/SSB complex and can suppress even when PARP1 catalysis is inhibited. In conclusion, XRCC1 suppresses the PARP1/SSB complex via PARP1 catalysis‐dependent and independent mechanisms. [ABSTRACT FROM AUTHOR]

Patients with a low micro-RNA-181d (miRNA-181d) level in glioblastoma tissue benefit most of carmustine wafer use. The study compares preoperative miRNA-181d plasma and tumor expression. This may form the base to decide, from a preoperative blood test, if carmustine wafer implantation is recommendable. A total of 60 patients suffering from glioblastoma treated between 2018 and 2020 were enrolled prospectively. Preoperatively, blood was drawn and the plasma was isolated. Tumor specimens were collected. Blood samples from 30 healthy individuals served as a reference. MiRNA-181d expression in plasma and tumor were acquired as fold change, using quantitative reverse transcription-polymerase chain reaction. Results were correlated with relevant demographic, clinical, and histopathologic aspects of the cohort. Further factors like tumor volume as well as blood panel results were considered. The Cancer Genome Atlas analysis was performed to investigate specific miRNA-181d-protein interactions to elude how miRNA-181 impact therapy response to carmustine. Patients with glioblastoma showed a significant overexpression of miRNA-181d compared with healthy individuals (P = 0.029). There was a significant correlation between miRNA-181d expression in tumor tissue and plasma (P = 0.001, R = 0.51). The sensitivity of low miRNA-181d expression in plasma predicting low miRNA-181d tumor expression was 76.6%. Tumor volume, preoperative medication, and items of blood panel analysis did not influence the prognostic value of plasma miRNA-181d expression. The Cancer Genome Atlas analysis revealed 8 potential protein targets to be regulated by miRNA-181d. miRNA-181d seems to be a potential molecular marker that can reliably be detected in blood samples of patients with glioblastoma. It should therefore prospectively be evaluated as a potential preoperative prognostic marker regarding carmustine wafer implantation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Carmustine is a chemotherapeutic agent that is mainly used in the treatment of glioblastoma and can cause toxic effects on various organs, including the liver. The white mulberry extract has anti-apoptotic and anti-oxidant effects. OBJECTIVE: The study aimed at investigating the effects of the dried white mulberry extract on the pathology, apoptosis, and oxidative stress in the liver, as well as the levels of serum adenosine deaminase, glutathione peroxidase, superoxide dismutase, ceruloplasmin, paraoxonase, and malondialdehyde in carmustine-administrated rats. METHODS: Forty-two rats divided into six groups were used in this study. BCNU was administrated intraperitoneally (IP) (5 mg/kg body weight (BW)/week) for 10 weeks to the BCNU and BCNU-DWME groups. DWME was administered (600 mg/kg-BW by oral gavage) daily for 10 weeks to the DWME and BCNU-DWME groups. After the experimental procedure, histopathological, immunohistochemical, and biochemical analyses were performed. RESULTS: Carmustine caused biliary hyperplasia at a dose of 5 mg/kg. However, the mulberry extract was not effective in alleviating this pathology. Furthermore, the administration of carmustine induced apoptosis in hepatocytes, and the mulberry extract had an anti-apoptotic effect. Carmustine increased the 8-OHdG activity in the liver, and dried mulberry extract ameliorated this activity. Although there was no significant difference in the serum oxidative stress parameters between the groups, carmustine significantly increased the adenosine deaminase activity during the recovery period, while mulberry extracts partially ameliorated these effects in the recovery period. CONCLUSIONS: Dried white mulberry extract has anti-apoptotic and anti-oxidative effects against carmustine-induced toxicity. [ABSTRACT FROM AUTHOR]

Density functional theory method combined with docking and molecular dynamics simulations are used to understand the interaction of carmustine with human glutathione reductase enzyme. The active site of the enzyme is evaluated by docking simulation is used for molecular dynamics simulation to deliver the carmustine molecule by (5,5) single walled carbon nanotube (SWCNT). Our model of carmustine in the active site of GR gives a negative binding energy that is further refined by QM/MM study in gas phase and solvent phase to confirm the stability of the drug molecule inside the active site. Once released from SWCNT, carmustine forms multiple polar and non-polar hydrogen bonding interactions with Tyr180, Phe209, Lys318, Ala319, Leu320, Leu321, Ile350, Thr352 and Val354 in the range of 2–4 Å. The SWCNT vehicle itself is held fix at its place due to multiple pi-pi stacking, pi-amide, pi-sigma interactions with the neighboring residues. These interactions in the range of 3–5 Å are crucial in holding the nanotube outside the drug binding region, hence, making an effective delivery. This study can be extended to envisage the potential applications of computational studies in the modification of known drugs to find newer targets and designing new and improved controlled drug delivery systems. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL) patients and some aggressive B-cell NHL as frontline therapy. Due to the shortage of carmustine, we switched to idarubicin-substituted BEAC (IEAC) conditioning regimen. We retrospectively compared the outcomes of 72 aggressive B-cell NHL patients treated with IEAC or BEAC regimens followed by ASCT as upfront consolidative treatment. The median time to neutrophil and platelet reconstitution showed no difference between IEAC and BEAC groups. IEAC regimen was well tolerated without increase of adverse events. Transplant-related mortality didn't occur. The overall survival (OS) and progression-free survival (PFS) of IEAC group (33 and 23 months) were a little longer than that of BEAC group (30 and 18 months). However, due to the small sample numbers, there's no significant difference in OS and PFS between IEAC and BEAC group with DLBCL or MCL. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase level, remission of disease, modified regimen were related with PFS and OS. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could be an alternative when carmustine was not available. [ABSTRACT FROM AUTHOR]

Although several studies have attempted to deduce by theoretical calculations the reaction mechanism of carmustine with DNA, no study has presented data on the reaction sites and the behavior of the electrons of the participating molecules. Thus, the objective of this paper is to apply the NBO (Natural Bond Orbital) model from the donor-acceptor point of view and the QTAIM (Quantum Theory: Atoms in Molecules) theory from the Laplacian of electronic density and the energy partition formalism IQA (Interacting Quantum Atoms) to quantify the interactions present in the alkylation between carmustine and DNA. The results showed that the decomposition of carmustine forms the chloroethyl ion and the 2-chloroethyldiazene hydroxide molecule, which subsequently breaks down to form 2-chloroethanol and N2. The NBO, QTAIM, and IQA data demonstrated that the ionic carbon of the chloroethyl ion suffers a nucleophilic attack from the O6-guanine. In the alkylation between intermediate 1,O6-ethanoguanine and cytosine, the bond between the CO of the intermediate ring breaks with a subsequent nucleophilic attack of the N of the cytosine with the C of the ring of the molecule 1,O6-ethanoguanine, forming a bridge of ethane between the guanine and cytosine bases. [ABSTRACT FROM AUTHOR]

Folliculotropic mycosis fungoides is a variant of cutaneous T-cell lymphoma characterized as having a folliculocentric infiltrate of malignant T cells along with a worse prognosis in comparison to the epidermotropic variants. Patients with advanced forms of folliculotropic mycosis fungoides are often poorly responsive to both skin-directed as well as to systemic therapies. We report here a high response rate using a novel therapeutic regimen combining interferon gamma, isotretinoin in low dose and topical carmustine, and in some cases concomitant skin-directed therapies, among 6 consecutive patients with refractory folliculotropic mycosis fungoides with stages IB through IIIB who had previously failed both topical and systemic therapies. The potential mechanisms of this multimodality approach are discussed. [ABSTRACT FROM AUTHOR]

Background: Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL.Methods: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS).Results: The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts.Conclusion: In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival. [ABSTRACT FROM AUTHOR]

Background: Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. Study Design and Treatment: This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled 90Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq 90Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq 90Y-daclizumab followed by high-dose chemotherapy and ASCT. Results: All 4 evaluable patients treated with 90Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Discussion: Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and 90Y-daclizumab provided strong enough β emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong β irradiation killed normal cells in the tumor microenvironment. Conclusions:90Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Significance: Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of 90Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. 90Y provided strong β emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong β radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of 90Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL. [ABSTRACT FROM AUTHOR]

Cancer of the lung is from the highest cancer type's incidence. It represents a high therapeutic challenge. Considerable adverse effects and cytotoxicity of highly potent drugs for healthy tissue require the development of novel drug delivery systems to improve pharmacokinetics and result in selective distribution of the loaded agent. Targeted therapy is a novel maneuver to achieve proper selectivity index. And as the main goal of nanocarriers is to target specific sites and improve the circulation time of the drug which is entrapped, encapsulate or conjugate in the carrier system so we chose nanoliposome as a drug carrier. Liposomes improved a potent drug targeting successfully in the last decade, but nanoliposomes offer more surface area and they have more solubility, improve controlled release, enhance bioavailability, and permit precision targeting of the material that is encapsulated to a greater extent. The study aims and objectivesis formulation of HER2 Ab directed nanosphere carrier for a combined Carmustine-busulfan and trastuzumab (LCBT), then Assessing antineoplastic efficacy of (LCBT) in lung carcinoma cell line. From the above results, we conclude that the LCBT has a prominent anticancer effect in lung A549 cancer cell line as it significantly decreased the growth percentage and show apoptotic effects. [ABSTRACT FROM AUTHOR]

Gliomas are the most common brain tumors in humans. Different chemotherapeutics are available to treat gliomas. However, they are costly and pose numerous side effects. The development of nanocomposite based on chemotherapeutic drug and metallic nanoparticle loaded with polymer could be highly useful against glioma. In this study, carmustine loaded with gold NPs and linked with PLGA-PSPE was produced as a bio-nanocomposite and its efficacy in treating glioma and burn wound were investigated. The synthesized biocomposite was characterized by biophysical techniques. It was observed that the synthesized composite was hexagonal and crystalline nature. TGA analysis showed that the particle had good combustible property. Interestingly, the Cm-Au-PLGA-PSPE composite had exhibited remarkable anti-tumor property against U251 human glioma. The flow cytometry showed a greater increase in the apoptosis rate (62.31%) of glioma cells exposed to the bio-nanocomposite. In addition, a greater reduction in the viability of U251 cells was recorded following treatment with Cm-Au-PLGA-PSPE composite. Quick healing of the heart, liver, spleen, lung and kidney tissue wounds in mouse was noticed with Cm-Au-PLGA-PSPE composite treatment. This study concludes that the newly produced Cm-Au-PLGA-PSPE composite would be a promising alternative in treating human gliomas and associated wounds with increased biomedical applications. [ABSTRACT FROM AUTHOR]

Molecular Dynamics simulation has been performed to study the effect of temperature on anti-cancer drug, carmustine, mediated by a graphene sheet. Root mean square deviation has been analysed at various temperatures, which is suggestive of the stability of the drug-graphene conjugate even at higher temperatures, although elevated diffusion of the drug at higher temperature has been observed as expected. Density functional theory is instrumental in determining the energetics of the drug action– from the generation of the active reacting species to the alkylation of DNA. By the energy profile, based on DFT, it is confirmed that it is the N7 site in guanine of the DNA major groove where the drug binds preferentially. The results provide a definitive insight into the release process as well as the effects of the chemotherapeutic carmustine drug and targets at generating a wholistic approach of drug-action. Image 1 • Molecular Dynamics (MD) simulation study of anti-cancer drug mediated by graphene. • Effect of temperature on carmustine drug release process. • DFT study of reaction of drug with guanine. • Energy profile and reaction energies are reported. [ABSTRACT FROM AUTHOR]

Density functional theory calculations were carried out to study the degradation mechanism of anticancer drug carmustine in an aqueous medium. The calculations indicate that the overall activation barrier for the degradation process is in the order of path A > path C (2H2O) > path C (0H2O) > path C (1H2O) > path H7 > path H8 > path B of proposed degradation pathways. In addition, the activation barrier is lower in all cases for the trans-mode of carmustine, and this isomer can proceed to any of the degradation paths with a faster kinetic than of the cis isomer. [ABSTRACT FROM AUTHOR]

• The conversion mechanism of anti-cancer medicine carmustine has been investigated. • The activation energy barrier for conversion is investigated. • The cis isomer is more stable thermodynamically. The conversion mechanism of cis and trans isomeric forms of anti-cancer medicine carmustine have been investigated. The density functional theory calculations were carried out utilizing the double-hybrid method of Grimme's B2PLYP combined with Grimme's D3BJ dispersion and with the basis set of def2-QZVP. According to the obtained results, the trans carmustine in the gas phase by acquiring 21.00 kcal mol−1 can overcome the nitrosyl rotation activation barrier and convert to the cis isomer. The resulting cis form by releases 2.77 kcal mol−1 of energy for gas phase is more stable than the trans carmustine. Moreover, by applying water as a solvent field, it is clear that water molecules by forming hydrogen bonds with the drug would stabilize the trans form by about 1.30 kcal mol−1. In this situation, the conversion activation barrier reaches to 17.22 kcal mol−1 which is 3.77 kcal mol−1 lower than this value for the gaseous state. [ABSTRACT FROM AUTHOR]

Abstract Wheat germ agglutinin (WGA) and folic acid (FA)-grafted methoxy poly(ethylene glycol) (MPEG)‑poly(ε‑caprolactone) (PCL) nanoparticles (WFNPs) were applied to transport anticancer drugs across the blood–brain barrier and treat glioblastoma multiforme (GBM). PCL was copolymerized with MPEG, and MPEG-PCL NPs were stabilized with pluronic F127 using a microemulsion-solvent evaporation technique and crosslinked with WGA and FA. The targeting ability of WFNPs loaded with etoposide (ETO), carmustine (BCNU) and doxorubicin (DOX) was investigated via the binding affinity of drug-loaded NP formulations to N ‑acetylglucosamine expressed in human brain microvascular endothelial cells and to folate receptor in malignant U87MG cells. We found that a shorter PCL chain in drug-loaded MPEG-PCL NPs yielded a smaller average size of the particles. An increase in PCL chain length (stronger hydrophobicity) enhanced drug entrapment efficiencies in MPEG-PCL NPs, and reduced drug-releasing rates from NP formulations. In addition, anti-proliferative activity against U87MG cells for the 3 drugs followed the order of WFNPs > FA-grafted NPs > WGA-grafted NPs > MPEG-PCL NPs. Immunofluorescence staining revealed that the ligands of drug-loaded WFNPs connected to N ‑acetylglucosamine and folate receptor with the help of surface WGA and FA. WFNPs carrying ETO, BCNU and DOX acted as dual-targeting nanocarriers, and their use can be a promising approach to inhibiting GBM growth in the brain. Highlights • Wheat germ agglutinin (WGA) and folic acid (FA)-grafted MPEG-PCL nanoparticles (WFNPs) are fabricated. • WFNPs assisted in delivering three anticancer drugs to glioblastoma multiforme (GBM). • Surface modified with WGA promoted the BBB permeation and with FA facilitated target site on U87MG cells. • Anti-proliferation against U87MG cells followed the order of WFNPs > FA-grafted NPs > WGA-grafted NPs > MPEG-PCL NPs. [ABSTRACT FROM AUTHOR]

Abstract In the present work, we apply density functional theory (DFT) calculations to investigate the drug delivery performance of the boron nitride nanotube (BNNT) having hydroxyl functional groups (-OH) for Carmustine (BCNU) agent in the gas phase and water environment. Based on the DFT results, it is found that the interaction between BCNU molecule and functionalized boron nitride nanotube (f-BNNT) is weak; so that, the adsorption of the BCNU drug on the nanotube surface is typically physisorption. Based on the structural characteristics, the stability of the BCNU/f-BNNT complexes contributed to the formation of the intermolecular hydrogen bonds (HBs) between the BCNU drug and hydroxyl groups of BNNT which confirmed by Bader theory of atoms in molecules (QTAIM) results. Our theoretical results show that the structural properties of BCNU molecule doesn't significantly change upon adsorption of drug molecule on f-BNNT. Moreover, the natural bond orbital (NBO) analysis show in BCNU/f-BNNT complexes, the charge transfers from f-BNNT to Carmustine drug and the electronic properties of BCNU drug are not affected during the adsorption process on the nanotube surface. Finally, the effects of drug concentration and temperature on the adsorption mechanism of BCNU molecules are investigated by molecular dynamics (MD) simulation. Such results provide valuable information on the potential applications of functionalized boron nitride nanotubes in the fields of drug delivery within biological systems. Highlights • The physical nature of drug adsorption on the f-BNNT. • BCNU can be formed intermolecular HBs with hydroxyl groups of BNNT. • By increasing drug concentration, the stabilities of complexes increase. [ABSTRACT FROM AUTHOR]

Glioma is extremely difficult to be completely excised by surgery due to its invasive nature. Thus, chemotherapy still is the mainstay in the treatment of glioma after surgery. However, the natural blood-brain barrier (BBB) greatly restricts the penetration of chemotherapeutic agents into the central nervous system. As a front-line anti-glioma agent in clinical, carmustine (BCNU) exerts antitumor effect by inducing DNA damage at the O 6 position of guanine. However, the therapeutic effect of BCNU was largely decreased because of the drug resistance mediated by O 6-alkylguanine-DNA alkyltransferase (AGT) and insufficient local drug concentrations. To overcome these obstacles, we synthesized a BCNU-loaded hypoxia-responsive nano-micelle with BBB penetrating capacity and AGT inhibitory activity, named as T80-HA-AZO-BG/BCNU NPs. In this nano-system, Tween 80 (T80) serves as a functional coating on the surface of the micelle, promoting transportation across the BBB. Hyaluronic acid (HA) with active tumor-targeting capability was linked with the hydrophobic O 6-benzylguanine (BG) analog via a hypoxia-sensitive azo bond. Under hypoxic tumor microenvironment, the azo bond selectively breaks to release O 6-BG as AGT inhibitor and BCNU as DNA alkylating agent. The synthesized T80-HA-AZO-BG/BCNU NPs showed good stability, favorable biocompatibility and hypoxia-responsive drug-releasing ability. T80 modification improved the transportation of the micelle across an in vitro BBB model. Moreover, T80-HA-AZO-BG/BCNU NPs exhibited significantly enhanced cytotoxicity against glioma cell lines with high AGT expression compared with traditional combined medication of BCNU plus O 6-BG. We expect that the tumor-targeting nano-micelle designed for chloroethylnitrosourea will provide new tools for the development of effective glioma therapy. [Display omitted] • A multifunctional tumor targeting nanocarrier was synthesized for delivery of BCNU. • The nanocarrier disintegrates under tumor hypoxia and releases the loaded drug. • Hyaluronic acid was linked to the nanocarrier for targeting CD44 in tumor cells. • Tween 80 was coated on the surface of nanocarrier to facilitate transport across BBB. • Tumor targeting and drug resistance reversal can be achieved for CENU therapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract O 6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes the alkyl groups from the O 6 position of guanine and is then degraded via ubiquitin-mediated degradation. Previous studies indicated that 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) facilitates the ubiquitination and degradation of MGMT in several types of cancer cells. However, the underlying mechanism of MGMT ubiquitination remains unclear. In this study, we demonstrated for the first time that ubiquitin-conjugating enzyme E2 B (UBE2B) is a novel regulator of MGMT ubiquitination mediated by BCNU in nasopharyngeal carcinoma (NPC) cells. The E3 ubiquitin ligase RAD18, a partner of UBE2B, is also involved in BCNU-mediated MGMT ubiquitination. Overexpression/knockdown of UBE2B enhanced/reduced BCNU-mediated MGMT ubiquitination. Surprisingly, UBE2B knockdown significantly increased BCNU cytotoxicity in NPC cells. Therefore, loss of UBE2B seems to disrupt ubiquitin-mediated degradation of alkylated MGMT. We found that UBE2B knockdown reduced MGMT activity, suggesting that loss of UBE2B leads to the accumulation of deactivated MGMT and suppresses MGMT protein turnover in BCNU-treated cells. These findings indicate that UBE2B modulates sensitivity to BCNU in NPC cells by regulating MGMT ubiquitination. [ABSTRACT FROM AUTHOR]

Background: Toxicity of carmustine and cyclophosphamide can cause pulmonary injury after hematopoietic stem cell transplantation.Objective: To evaluate the radiologic findings of pulmonary injuries following carmustine- and cyclophosphamide-based preparative regimens in children.Materials and Methods: From 2010 to 2014, 35 children received carmustine- and cyclophosphamide-based preparative regimens. Fourteen of 35 children presented with symptoms and radiologic abnormalities. Eight of 14 children had no evidence of infection, cardiogenic edema, or other explainable causes. We retrospectively analyzed their chest radiographs and CT scans for ground-glass opacity, consolidation, septal thickening and pleural effusion.Results: Major chest radiographic findings were bilateral diffuse ground-glass opacity (n=8) and septal thickening (n=7). CT findings were multifocal patchy (n=4) or inhomogeneously diffuse (n=4) ground-glass opacity, multifocal consolidations (n=7) and septal thickening (n=7). All of these lesions at CT were bilateral, but showed lower lobe predominance in 88, 100, and 63%, respectively. There was no central/peripheral or anterior/posterior predilection. Six children had small pleural effusions, which were bilateral in five children.Conclusion: Bilateral ground-glass opacity with or without consolidation, septal thickening and pleural effusion were common radiologic findings in pulmonary injury following carmustine- and cyclophosphamide-based preparative regimens. [ABSTRACT FROM AUTHOR]

The combination of carmustine, etoposide, aracytin, and melphalan(BEAM) conditioning regimen in autologous stem-cell transplantation (ASCT) is widely used in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. It is also an option in patients with very-high risk aggressive NHL in first complete remission (CR). Recently, a phase Ib-II feasibility study using bendamustine replacing carmustine (BCNU) was reported. We report herein a safety and efficacy analysis of bendamustine-EAM (BeEAM) with a control BEAM counterpart paired cohort (1/2). One hundred and two patients were analyzed. Overall survival (OS) and progression-free survival (PFS) were not reached and seemed to be comparable between both groups. However, grade III or greater diarrhea was significantly higher in BeEAM patients (44 vs. 15%, p = .002). The median number of days with fever >38 °C was significantly higher in BeEAM group (5.5 vs. 2, p < .001). This case-control study suggests that BeEAM followed by ASCT using bendamustine at 100 mg/m2/d is effective but has a different toxicity profile than the BEAM regimen. [ABSTRACT FROM AUTHOR]

Randomized, controlled trials have shown significant improvement of survival after implantation of 1,3-bis(2-Chloroethyl)-1-nitrosourea (BCNU) wafers for patients suffering from high-grade glioma. A combination of local chemotherapy with BCNU and concomitant radiochemotherapy with temozolomide (TMZ) appears to be attractive to enhance the overall survival, even though these treatments may potentially cumulate their toxicity.We report a clinical case of a patient submitted to this combined treatment protocol. Severe brain edema and a cystic formation in the surgical cavity rapidly developed. Data supporting the use of Gliadel® combined with TMZ comes from small retrospective studies, and some series have shown a very high rate of adverse events (AEs) when this multimodality treatment is applied. Combined protocols of local and systemic chemotherapy might provide survival benefits, although AEs seem currently underestimated. [ABSTRACT FROM AUTHOR]

Highlights • We studied the effects of fotemustine substitution in BEAM, prompted by BCNU shortage. • BEAM and FEAM did not appear different in terms of survival and disease control. • FEAM resulted in higher rates of gastrointestinal and infectious toxicities. • Mortality from infection was higher with FEAM, due to more sepsis from Gram-negative bacteria. • FEAM is an acceptable alternative to BEAM but is not justified when BCNU is available. Graphical Abstract Unlabelled image Abstract BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P <.001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P =.017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P <.001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P <.001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM =.1 versus FEAM =.19, P <.001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P =.42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P =.04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply. [ABSTRACT FROM AUTHOR]

Highlights • TBC-ASCT patients have a higher risk of DNA virus infections compared with BEAM-ASCT. • Fungal and parasitic infections appear more common after TBC-ASCT. • Clinicians should be aware of the differences in infections between BEAM- and TBC-ASCT patients. Abstract We investigated the incidence of viral, fungal, bacterial, and parasitic infections observed in 57 patients with central nervous system lymphoma after thiotepa, busulfan, and cyclophosphamide-conditioned autologous stem cell transplantation (TBC-ASCT) and 79 patients with systemic non-Hodgkin lymphoma after traditional carmustine, etoposide, cytarabine, and melphalan–conditioned ASCT (BEAM-ASCT). Twenty of 57 (35%) TBC-ASCT patients had detectable viremia with human herpesvirus 6, cytomegalovirus, adenovirus, or BK virus, versus 9 of 79 (11%) BEAM-ASCT patients. Eight TBC-ASCT patients had clinically relevant viral infections (4 human herpesvirus 6, 2 cytomegalovirus, 1 adenovirus, 2 BK virus), versus 0 in the BEAM-ASCT group. Four TBC-ASCT patients suffered infections from either a fungal or parasitic pathogen versus 1 BEAM-ASCT patient. TBC was associated with greater risk of viral reactivation compared with BEAM, independent of other factors (hazard ratio, 4.42; 95% confidence interval, 1.9 to 11.3; P <.001). Prolonged lymphopenia and steroid use in the peri- and post-ASCT period did not explain these observed differences. The pathogenesis of these unusual infections in TBC-ASCT patients remains incompletely understood, and may involve more potent immune suppression with TBC conditioning. Clinicians should be aware of these differences in infection risk in TBC-ASCT patients, which more closely parallel those seen in allogenic hematopoietic cell transplantation recipients. New prophylactic approaches to help minimize these infections should be considered in this population. [ABSTRACT FROM AUTHOR]

Chemo-refractory NHL has a very poor outcome; the addiction of RIT to salvage regiment pre ASCT had recently demonstrated promising results.We performed a retrospective sequential study to determine the feasibility of standard Zevalin with BEAM in high-risk relapse/refractory NHL. A matched cohort analysis with a group treated with standard BEAM without Zevalin was performed as secondary endpoint. Between October 2006 and January 2013, 37 NHL patients at high risk for progression or early (< 1 year) or multiple relapses were treated with Z-BEAM and ASCT after R-DHAP or R-ICE as salvage therapy. Clinical characteristics were 19 refractory and 18 early or multiple relapse; 16 patients received 1, and 21 had 2 or more previous rituximab-containing chemotherapy. At the end of treatment, response was CR 22 (59%), PR 10 (27%), PD 4 (11%), and toxic death (TD) 1 (3%). With a median follow up of 61 months, 3-year PFS was 61% and OS 61%. Fifteen patients died, 12 of lymphoma. Comparison with 21 treated with BEAM alone showed a numerical higher 3-yr PFS rate in favor of Z-BEAM but not statistically significant (57 vs 48%). With the limitation of the small sample subgroup analysis, a significant benefit was observed in relapsed patients for PFS (78% Z-BEAM vs 22% BEAM p = 0.016) and OS (83% Z-BEAM vs 22% BEAM p = 0.001). In relapsed/refractory high-risk NHL, Z-BEAM+ASCT is able to achieve a good ORR. Three-year PFS is promising for early relapsed patients but is not satisfactory for those with refractory disease. [ABSTRACT FROM AUTHOR]

Carnosic acid (CA), a major polyphenolic diterpene present in Rosmarinus officinalis, has been reported to have multiple functions, including antitumor activity. The MTT assay, BrdU incorporation, wound healing, and colony formation were used to detect melanoma B16F10 cell growth and proliferation. Flow cytometry was used for cell cycle detection. p21 and p27 expression was detected byWestern blotting. B16F10 cell xenograftmodel was established, and treated with CA, carmustine (BCNU), or lomustine (CCNU). The present study found that CA exhibits significant growth inhibition and cell cycle arrest in melanoma B16F10 cells. We also found that CA triggers cell cycle arrest at G0/G1 phase, and enhances p21 expression. Additionally, CA can enhance BCNU- and CCNU-mediated cytotoxicity and cell cycle arrest in B16F10 cells. Finally, we found that CA inhibits tumor growth, and reduces the values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in vivo. The present study study concluded that CA may be safe and useful as a novel chemotherapeutic agent. [ABSTRACT FROM AUTHOR]

In the present study, it is attempted to scrutinize the hydrogen bonding interaction between Carmustine drug and DNA pyrimidine bases by means of density functional theory calculations regarding their geometries, binding energies, vibrational frequencies, and topological features of the electron density in the gas phase and the water solution. Based on the density functional theory results, it is found that the process of intermolecular interaction between Carmustine drug and nucleobases is exothermic and all of the optimized configurations are stable. Furthermore, the negative stability energy represented by a polarizable continuum model shows the significant increase in the solubility of the nucleobase after hydrogen bonding intermolecular interaction in the presence of water solvent. It is also found that the intermolecular hydrogen bonds between drug and the nucleobases play the significant role in the stability of the physisorption configurations. Hydrogen bond energies for hydrogen-bonded complexes are obtained from Espinosa method and the atoms-in-molecules theory are also applied to get a more precise insight into the nature of the intermolecular hydrogen bond interactions. [ABSTRACT FROM AUTHOR]

Hodgkin lymphoma (HL) patients failing after high dose chemotherapy (HDC) and auto-SCT have a poor outcome. Some patients may still benefit from further treatments. From 1996 to 2016, 137 HL patients (39.5%) out of 347 transplanted experienced post auto-SCT failure. Males/female 61%:39%, median age at auto-SCT 23.4 years and median follow-up 55.6 months (9-153). Type of failure was progressive (46%), relapsed (35%) or persistent disease/refractory disease (19%). Median overall survival (OS) from the time of failure is 20 months; 35 patients (25.5%) are alive. One hundred and four patients received treatment; the response rate was 45%; complete remission in 41 (30%) and partial remission in 21 (15%) patients. 1st interventions post auto-SCT were chemotherapy (39%), radiation therapy (35%) or best supportive care (24%). Twenty-seven patients with 2nd-SCT (allogeneic (15), auto-SCT (2)) and/or brentuximab (18 patients) had superior OS (50.6 months) vs other treatments (22.5 months, P value 0.037). COX regression multivariate analysis identified post auto-SCT treatment failure before 12 months (hazard ratio (HR) 3.37, CI 1.7-6.6, P value < 0.001), presence of B symptoms (HR 2.55, CI 1.4-4.6, P value 0.002), stages III-IV (HR 2.7, CI 1.5-4.9, P value 0.001), albumin < 4 g/dl (HR 1.76, CI 1.1-2.9, P value 0.027) and tumor > 5 cm (HR 1.1.9, CI 1.13-3.25, P value 0.015) as significant risk factors; P value < 0.001. KM OS with 0-1 factor (148.6 months): 2 factors (23.6 months) and 3-5 factors (9.4 months) (P value < 0.001). OS was 63%:25%:7% respectively with 0-1:2:3-5 factors respectively (P value < 0.001). Despite high-risk factors, 2nd-SCT/brentuximab use post HDC auto-SCT failure may result in durable survival. [ABSTRACT FROM AUTHOR]