Combined Theoretical and Experimental Investigations: Design, Synthesis, Characterization, and In Vitro Cytotoxic Activity Assessment of a Complex of a Novel Ureacellobiose Drug Carrier with the Anticancer Drug Carmustine.

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-(ß-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.

A Tween-80 modified hypoxia/esterase dual stimulus-activated nanomicelle as a delivery platform for carmustine - Design, synthesis, and biological evaluation.

As a clinical anti-glioma agent, the therapeutic effect of carmustine (BCNU) was largely decreased because of the drug resistance mediated by O6-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 (O6-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 IC50 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.

Clinical Course after Carmustine Wafer Implantation for Newly Diagnosed Adult-type Diffuse Gliomas; A controlled propensity matched analysis of a single center cohort.

PURPOSE: It remains unclear whether combining carmustine wafer (CW) implantation with the standard treatment for adult-type diffuse gliomas is safe and has a prognostic impact. This study aimed to investigate the prognostic value and safety of CW implantation. METHODS: Adult patients with IDH-wild-type and -mutant gliomas, grades 3-4 treated with surgical resection, radiotherapy, and temozolomide chemotherapy between 2013 and 2023 were surveyed. CWs were implanted except in cases of intraoperative wide ventricle opening or marked preoperative brain swelling. For survival analyses, a case-matched dataset based on propensity score matching (PSM), including multiple factors (patient background, diagnosis, and extent of resection) was generated. Progression-free survival (PFS), overall survival (OS), and frequency of complications of CW implantation (brain edema, infection, and cerebrospinal fluid leakage) were compared between the CW and non-use groups. RESULTS: In total, 127 patients (75 in the CW use group and 52 in the non-use group) were enrolled. Regardless of stratification, no significant differences in PFS and OS were observed between the CW use and non-use groups. The frequency of postoperative brain edema was significantly higher in the CW use group than in the non-use group. An adjusted dataset containing 41 patients in the CW use and nonuse groups was generated. Even after PSM, CW implantation had no prognostic effect. CONCLUSIONS: CW implantation with standard treatment demonstrated little beneficial effect for the present strategy of CW use.

BeEAM vs. BEAM: evaluating conditioning regimens for autologous stem cell transplantation in patients with relapsed or refractory DLBCL.

PURPOSE: To evaluate whether BeEAM is an alternative to BEAM for autologous stem cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). METHODS: Data of 60 patients with relapsed or refractory DLBCL who underwent ASCT from January 2018 to June 2023 in our center, including 30 patients in the BeEAM group and 30 patients in the BEAM group, were retrospectively analyzed. The time to hematopoietic reconstitution, treatment-related adverse events, number of hospitalization days, hospitalization cost, and survival benefit were compared between the two groups. RESULTS: The clinical characteristics of the patients did not significantly differ between the two groups. The median number of reinfused CD34 + cells was 5.06 × 106/kg and 5.17 × 106/kg in the BeEAM and BEAM groups, respectively, which did not significantly different (p = 0.8829). In the BeEAM and BEAM groups, the median time to neutrophil implantation was 10.2 and 10.27 days, respectively (p = 0.8253), and the median time to platelet implantation was 13.23 and 12.87 days, respectively (p = 0.7671). In the BeEAM and BEAM groups, the median hospitalization duration was 30.37 and 30.57 days, respectively (p = 0.9060), and the median hospitalization cost was RMB 83,425 and RMB 96,235, respectively (p = 0.0560). The hospitalization cost was lower in the BeEAM group. The most common hematologic adverse events were grade ≥ 3 neutropenia and thrombocytopenia, whose incidences were similar in the two groups. The most common non-hematologic adverse events were ≤ grade 2 and the incidences of these events did not significantly differ between the two groups. Median overall survival was not reached in either group, with predicted 5-year overall survival of 72.5% and 60% in the BeEAM and BEAM groups, respectively (p = 0.5872). Five-year progression-free survival was 25% and 20% in the BeEAM and BEAM groups, respectively (p = 0.6804). CONCLUSION: As a conditioning regimen for relapsed or refractory DLBCL, BeEAM has a desirable safety profile and is well tolerated, and its hematopoietic reconstitution time, number of hospitalization days, and survival benefit are not inferior to those of BEAM. BeEAM has a lower hospitalization cost and is an alternative to BEAM.

Regional shear wave speeds track regional axial stress in nonuniformly loaded fibrous soft tissues.

Ligaments and tendons undergo nonuniform deformation during movement. While deformations can be imaged, it remains challenging to use such information to infer regional tissue loading. Shear wave tensiometry is a promising noninvasive technique to gauge axial stress and is premised on a tensioned beam model. However, it is unknown whether tensiometry can predict regional stress in a nonuniformly loaded structure. The objectives of this study were to (1) determine whether regional shear wave speed tracks regional axial stress in nonuniformly loaded fibrous soft tissues, and (2) determine the sensitivity of regional axial stress and shear wave speed to nonuniform load distribution and fiber alignment. We created a representative set of 12,000 dynamic finite element models of a fibrous soft tissue with probabilistic variations in fiber alignment, stiffness, and aspect ratio. In each model, we applied a randomly selected nonuniform load distribution, and then excited a shear wave and tracked its regional propagation. We found that regional shear wave speed was an excellent predictor of the regional axial stress (RMSE = 0.57 MPa) and that the nature of the regional shear wave speed-stress relationship was consistent with a tensioned beam model (R2 = 0.99). Variations in nonuniform load distribution and fiber alignment did not substantially alter the wave speed-stress relationship, particularly at higher loads. Thus, these findings suggests that shear wave tensiometry could provide a quantitative estimate of regional tissue stress in ligaments and tendons.

CDKN2A promoter methylation enhances self-renewal of glioblastoma stem cells and confers resistance to carmustine.

BACKGROUND: Glioblastoma, a highly aggressive form of brain cancer, poses significant challenges due to its resistance to therapy and high recurrence rates. This study aimed to investigate the expression and functional implications of CDKN2A, a key tumor suppressor gene, in glioblastoma cells, building upon the existing background of knowledge in this field. METHOD: Quantitative reverse transcription PCR (qRT-PCR) analysis was performed to evaluate CDKN2A expression in U87 glioblastoma cells compared to normal human astrocytes (NHA). CDKN2A expression levels were manipulated using small interfering RNA (siRNA) and CDKN2A overexpression vector. Cell viability assays and carmustine sensitivity tests were conducted to assess the impact of CDKN2A modulation on glioblastoma cell viability and drug response. Sphere formation assays and western blot analysis were performed to investigate the role of CDKN2A in glioblastoma stem cell (GSC) self-renewal and pluripotency marker expression. Additionally, methylation-specific PCR (MSP) assays and demethylation treatment were employed to elucidate the mechanism of CDKN2A downregulation in U87 cells. RESULT: CDKN2A expression was significantly reduced in glioblastoma cells compared to NHA. CDKN2A overexpression resulted in decreased cell viability and enhanced sensitivity to carmustine treatment. CDKN2A inhibition promoted self-renewal capacity and increased pluripotency marker expression in U87 cells. CDKN2A upregulation led to elevated protein levels of p16INK4a, p14ARF, P53, and P21, which are involved in cell cycle regulation. CDKN2A downregulation in U87 cells was associated with high promoter methylation, which was reversed by treatment with a demethylating agent. CONCLUSION: Our findings demonstrate that CDKN2A downregulation in glioblastoma cells is associated with decreased cell viability, enhanced drug resistance, increased self-renewal capacity, and altered expression of pluripotency markers. The observed CDKN2A expression changes are mediated by promoter methylation. These results highlight the potential role of CDKN2A as a therapeutic target and prognostic marker in glioblastoma.

Methodology for small animals targeted irradiations at conventional and ultra-high dose rates 65 MeV proton beam.

As part of translational research projects, mice may be irradiated on radiobiology platforms such as the one at the ARRONAX cyclotron. Generally, these platforms do not feature an integrated imaging system. Moreover, in the context of ultra-high dose-rate radiotherapy (FLASH-RT), treatment planning should consider potential changes in the beam characteristics and internal movements in the animal. A patient-like set-up and methodology has been implemented to ensure target coverage during conformal irradiations of the brain, lungs and intestines. In addition, respiratory cycle amplitudes were quantified by fluoroscopic acquisitions on a mouse, to ensure organ coverage and to assess the impact of respiration during FLASH-RT using the 4D digital phantom MOBY. Furthermore, beam incidence direction was studied from mice µCBCT and Monte Carlo simulations. Finally,in vivodosimetry with dose-rate independent radiochromic films (OC-1) and their LET dependency were investigated. The immobilization system ensures that the animal is held in a safe and suitable position. The geometrical evaluation of organ coverage, after the addition of the margins around the organs, was satisfactory. Moreover, no measured differences were found between CONV and FLASH beams enabling a single model of the beamline for all planning studies. Finally, the LET-dependency of the OC-1 film was determined and experimentally verified with phantoms, as well as the feasibility of using these filmsin vivoto validate the targeting. The methodology developed ensures accurate and reproducible preclinical irradiations in CONV and FLASH-RT without in-room image guidance in terms of positioning, dose calculation andin vivodosimetry.

Anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation in patients with high-risk CD30+ lymphoma: a phase 1 study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30+ lymphoma at high risk of relapse. METHODS: This phase 1 dose-escalation study was performed at two sites in the USA. Patients aged 3 years and older, with classical Hodgkin lymphoma or non-Hodgkin lymphoma with CD30+ disease documented by immunohistochemistry, and a Karnofsky performance score of more than 60% planned for autologous HSCT were eligible if they were considered high risk for relapse as defined by primary refractory disease or relapse within 12 months of initial therapy or extranodal involvement at the start of pre-transplantation salvage therapy. Patients received a single infusion of CAR T cells (2 × 107 CAR T cells per m2, 1 × 108 CAR T cells per m2, or 2 × 108 CAR T cells per m2) as consolidation after trilineage haematopoietic engraftment (defined as absolute neutrophil count ≥500 cells per µL for 3 days, platelet count ≥25 × 109 platelets per L without transfusion for 5 days, and haemoglobin ≥8 g/dL without transfusion for 5 days) following carmustine, etoposide, cytarabine, and melphalan (BEAM) and HSCT. The primary endpoint was the determination of the maximum tolerated dose, which was based on the rate of dose-limiting toxicity in patients who received CAR T-cell infusion. This study is registered with ClinicalTrials.gov (NCT02663297) and enrolment is complete. FINDINGS: Between June 7, 2016, and Nov 30, 2020, 21 patients were enrolled and 18 patients (11 with Hodgkin lymphoma, six with T-cell lymphoma, one with grey zone lymphoma) were infused with anti-CD30 CAR T cells at a median of 22 days (range 16-44) after autologous HSCT. There were no dose-limiting toxicities observed, so the highest dose tested, 2 × 108 CAR T cells per m2, was determined to be the maximum tolerated dose. One patient had grade 1 cytokine release syndrome. The most common grade 3-4 adverse events were lymphopenia (two [11%] of 18) and leukopenia (two [11%] of 18). There were no treatment-related deaths. Two patients developed secondary malignancies approximately 2 years and 2·5 years following treatment (one stage 4 non-small cell lung cancer and one testicular cancer), but these were judged unrelated to treatment. At a median follow-up of 48·2 months (IQR 27·5-60·7) post-infusion, the median progression-free survival for all treated patients (n=18) was 32·3 months (95% CI 4·6 months to not estimable) and the median progression-free survival for treated patients with Hodgkin lymphoma (n=11) has not been reached. The median overall survival for all treated patients has not been reached. INTERPRETATION: Anti-CD30 CAR T-cell infusion as consolidation after BEAM and autologous HSCT is safe, with low rates of toxicity and encouraging preliminary activity in patients with Hodgkin lymphoma at high risk of relapse, highlighting the need for larger studies to confirm these findings. FUNDING: National Heart Lung and Blood Institute, University Cancer Research Fund at the Lineberger Comprehensive Cancer Center.

Three-row MRI receive array with remote circuitry to preserve radiation transparency.

Objective.Up to this point, 1.5 T linac-compatible coil array layouts have been restricted to one or two rows of coils because of the desire to place radiation-opaque circuitry adjacent to the coils and outside the window through which the linac beam travels. Such layouts can limit parallel imaging performance. The purpose of this work was to design and build a three-row array in which remotely located circuits permitted a central row of coils while preserving the radiolucent window.Approach.The remote circuits consisted of a phase shifter to cancel the phase introduced by the coaxial link between the circuit and coil, followed by standard components for tuning, matching, detuning, and preamplifier decoupling. Tests were performed to compare prototype single-channel coils with remote or local circuits, which were followed by tests comparing two and three-row arrays .Main results.The single-channel coil with the remote circuit maintained 85% SNR at depths of 30 mm or more as compared to a coil with local circuit. The three-row array provided similar SNR as the two-row array, along with geometry factor advantages for parallel imaging acceleration in the head-foot direction.Significance.The remote circuit strategy could potentially support future MR-linac arrays by allowing greater flexibility in array layout compared to those confined by local circuits, which can be leveraged for parallel imaging acceleration.

Gemcitabine-based conditioning compared to BEAM/BEAC conditioning prior to autologous stem cell transplantation for non-Hodgkin lymphoma: No difference in outcomes.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains an effective treatment for non-Hodgkin lymphoma (NHL). The limited availability of carmustine has prompted the exploration of novel alternative conditioning regimens. This study aimed to compare the efficacy and safety profile of GBM/GBC (gemcitabine, busulfan, and melphalan or cyclophosphamide) conditioning compared with the standard BEAM/BEAC regimens (carmustine, etoposide, cytarabine, and melphalan or cyclophosphamide) for ASCT in patients with NHL. METHODS: A retrospective analysis was conducted on 231 NHL patients, who underwent ASCT from October 2010 to October 2021 at the Institute of Hematology & Blood Disease Hospital, including both first-line and salvage settings. This resulted in the inclusion of 112 patients in the GBM/GBC arm and 92 in the BEAM/BEAC arm. Propensity score matching was employed to validate the results. RESULTS: Disease subtype distribution was similar between the GBM/GBC and BEAM/BEAC groups, with diffuse large B-cell lymphoma being the most common (58.9% vs. 58.7%), followed by PTCL (17.0% vs. 18.5%) and MCL (14.3% vs. 14.1%). At 3 months post-ASCT, complete response (CR) rates were comparable (GBM/GBC 93.5% vs. BEAM/BEAC 91.1%; p = 0.607). The 4-year progression-free survival (78.4% vs. 82.3%; p = 0.455) and 4-year overall survival (88.1% vs. 87.7%; p = 0.575) were also similar. Both groups exhibited low non-relapse mortality at 4 years (GBM/GBC 1.8% vs. BEAM/BEAC 3.5%; p = 0.790) with no transplant-related mortalities reported. The GBM/GBC cohort demonstrated a higher incidence of grade 3/4 oral mucositis and hepatic toxicity, whereas the BEAM/BEAC group had more frequent cases of bacteremia or sepsis (13 cases vs. 5 in GBM/GBC). CONCLUSIONS: The GBM/GBC regimen is effective and well-tolerated, offering outcomes that are highly comparable to those in NHL patients conditioned with BEAM/BEAC, as demonstrated in a prognostically matched cohort.

Prognostic differences between carmustine, etoposide, cytarabine and melphalan (BEAM) and carmustine, etoposide, cytarabine, melphalan and fludarabine (BEAMF) regimens before autologous stem cell transplantation plus chimeric antigen receptor T therapy in patients with refractory/relapsed B-cell non-Hodgkin-lymphoma.

BACKGROUND AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Determination of thePrpand radial dose correction factor in reference dosimetry.

Objectives.In an addendum to AAPM TG-51 protocol, McEwenet al, (DOI:10.1118/1.4866223) introduced a new factorPrpto account for the radial dose distribution of the photon beam over the detector volume mainly in flattening filter free (FFF) beams.Prpand its extension to non-FFF beam reference dosimetry is investigated to see its impact in a clinical situation.Approches.ThePrpwas measured using simplified version of Sudhyadhomet al(DOI:10.1118/1.4941691) for Elekta and Varian FFF beams with two commonly used calibration detectors; PTW-30013 and Exradin-A12 ion chambers after acquiring high resolution profiles in detectors cardinal coordinates. For radial dose correction factor, the ion chambers were placed in a small water phantom and the central axis position was set to center of the sensitive volume on the treatment table and was studied by rotating the table by 15-degree interval from -90 to +90 degrees with respect to the initial (zero) position.Main results.The magnitude ofPrpvaries very little with machine, detector and beam energies to a value of 1.003 ± 0.0005 and 1.005 ± 0.0005 for 6FFF and 10FFF, respectively. The radial anisotropy for the Elekta machine with Exradin-A12 and PTW-30013 detector the magnitudes are in the range of (0.9995±0.0011 to 1.0015±0.0010) and (0.9998±0.0007 to 1.0015±0.0010), respectively. Similarly, for the Varian machine with Exradin-A12 and PTW-30013 ion chambers, the magnitudes are in the range of (1.0004±0.0010 to 1.0018±0.0018) and (1.0006±0.0009 to 1.0027±0.0007), respectively.Significance.ThePrpis ≤ 0.3% and 0.5% for 6FFF and 10FFF, respectively. The radial dose correction factor in regular beams also does not impact the dosimetry where the maximum magnitude is ±0.2% which is within experimental uncertainty.

Mini-GRID radiotherapy on the CLEAR very-high-energy electron beamline: collimator optimization, film dosimetry, and Monte Carlo simulations.

Objective.Spatially-fractionated radiotherapy (SFRT) delivered with a very-high-energy electron (VHEE) beam and a mini-GRID collimator was investigated to achieve synergistic normal tissue-sparing through spatial fractionation and the FLASH effect.Approach.A tungsten mini-GRID collimator for delivering VHEE SFRT was optimized using Monte Carlo (MC) simulations. Peak-to-valley dose ratios (PVDRs), depths of convergence (DoCs, PVDR ≤ 1.1), and peak and valley doses in a water phantom from a simulated 150 MeV VHEE source were evaluated. Collimator thickness, hole width, and septal width were varied to determine an optimal value for each parameter that maximized PVDR and DoC. The optimized collimator (20 mm thick rectangular prism with a 15 mm × 15 mm face with a 7 × 7 array of 0.5 mm holes separated by 1.1 mm septa) was 3D-printed and used for VHEE irradiations with the CERN linear electron accelerator for research beam. Open beam and mini-GRID irradiations were performed at 140, 175, and 200 MeV and dose was recorded with radiochromic films in a water tank. PVDR, central-axis (CAX) and valley dose rates and DoCs were evaluated.Main results.Films demonstrated peak and valley dose rates on the order of 100 s of MGy/s, which could promote FLASH-sparing effects. Across the three energies, PVDRs of 2-4 at 13 mm depth and DoCs between 39 and 47 mm were achieved. Open beam and mini-GRID MC simulations were run to replicate the film results at 200 MeV. For the mini-GRID irradiations, the film CAX dose was on average 15% higher, the film valley dose was 28% higher, and the film PVDR was 15% lower than calculated by MC.Significance.Ultimately, the PVDRs and DoCs were determined to be too low for a significant potential for SFRT tissue-sparing effects to be present, particularly at depth. Further beam delivery optimization and investigations of new means of spatial fractionation are warranted.

Association Between Diverse Cell Death Patterns Related Gene Signature and Prognosis, Drug Sensitivity, and Immune Microenvironment in Glioblastoma.

Glioblastoma (GBM) is the most invasive type of glioma and is difficult to treat. Diverse programmed cell death (PCD) patterns have a significant association with tumor initiation and progression. A novel prognostic model based on PCD genes may serve as an effective tool to predict the prognosis of GBM. The study incorporated 11 PCD patterns, namely apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, and oxeiptosis, to develop the model. To construct and validate the model, both bulk and single-cell transcriptome data, along with corresponding clinical data from GBM cases, were obtained from the TCGA-GBM, REMBRANDT, CGGA, and GSE162631 datasets. A cell death-related signature containing 14 genes was constructed with the TCGA-GBM cohort and validated in the REMBRANDT and CGGA datasets. GBM patients with a higher cell death index (CDI) were significantly associated with poorer survival outcomes. Two separate clusters associated with clinical outcomes emerged from unsupervised analysis. A multivariate Cox regression analysis was conducted to examine the association of CDI with clinical characteristics, and a prognostic nomogram was developed. Drug sensitivity analysis revealed high-CDI GBM patients might be resistant to carmustine while sensitive to 5-fluorouracil. Less abundance of natural killer cells was found in GBM cases with high CDI and bulk transcriptome data. A cell death-related prognostic model that could predict the prognosis of GBM patients with good performance was established, which could discriminate between the prognosis and drug sensitivity of GBM.

Functionalized Carbon Nano-Onions as a Smart Drug Delivery System for the Poorly Soluble Drug Carmustine for the Management of Glioblastoma.

The drug delivery system for transporting anticancer agents to targeted tissues in the body is a challenging issue. In search of a suitable biocompatible carrier having controlled and sustained drug release properties of poorly soluble drugs, carbon nano-onions (CNOs) were loaded with an anticancer drug, bis-chloroethyl nitrosourea (BCNU/carmustine). CNOs being autofluorescent, drug-loaded functionalized CNOs (f-CNO-BCNU) can be detected in vivo. Transmission electron microscopy (TEM) and differential light scattering (DLS) techniques were used to analyze the sizes of these f-CNOs. The molecular study revealed that the f-CNO-BCNU readily and noncovalently binds with the folate receptors present on the cancer cell surface in excess. Computer modeling and molecular dynamics simulation followed by binding free energy calculation shows f-CNOs have -29.9 kcal/mol binding free energy, and it noncovalently binds the receptor FRα using loop dynamics of three essential loops present in the protein along with polar stabilization interactions provided by Asp55 and Glu86 residues present in the active site. The f-CNO effectively decreased cancer cell viability with a low IC50 value (the concentration that led to 50% killing of the cells). The cell-based Franz diffusion assay was performed to study the drug release profile. The f-CNO-BCNUs also decreased the mitochondrial membrane potential of U87 cells, increased reactive oxygen species release, and caused a loss of mitochondrial membrane integrity. The f-CNOs also increased the percentage of apoptotic cells observed by the Annexin V assay. Based on observed results, it can be concluded that the f-CNO-BCNU efficiently targets the cancer cells, enhances the bioavailability of carmustine, and can be used as a smart chemotherapeutic agent. This strategy offers better patient compliance and greater bioavailability of the drug.

CEAC (oral semustine, etoposide, cytarabine and cyclophosphamide) vs BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning regimen of autologous stem cell transplantation for diffuse large B-cell lymphoma: a post-hoc, propensity score-matched, cohort study in Chinese patients.

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.

Identification of clinical factors impacting outcome in patients undergoing autologous hematopoietic cell transplantation after BEAM and TEAM conditioning.

Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto-HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety-six patients undergoing auto-HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto-HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT-CI score ≥ 4, and cardiac disease before auto-HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto-HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non-relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto-HSCT.