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Scientific Reports Oct 2022Microfluidic devices that combine an extracellular matrix environment, cells, and physiologically relevant perfusion, are advantageous as cell culture platforms. We...
Microfluidic devices that combine an extracellular matrix environment, cells, and physiologically relevant perfusion, are advantageous as cell culture platforms. We developed a hydrogel-based, microfluidic cell culture platform by loading polyethylene glycol (PEG) hydrogel-encapsulated U87 glioblastoma cells into membrane-capped wells in polydimethyl siloxane (PDMS). The multilayer microfluidic cell culture system combines previously reported design features in a configuration that loads and biomimetically perfuses a 2D array of cell culture chambers. One dimension of the array is fed by a microfluidic concentration gradient generator (MCGG) while the orthogonal dimension provides loading channels that fill rows of cell culture chambers in a separate layer. In contrast to typical tree-like MCGG mixers, a fractional serial dilution of 1, ½, ¼, and 0 of the initial solute concentration is achieved by tailoring the input microchannel widths. Hydrogels are efficiently and reproducibly loaded in all wells and cells are evenly distributed throughout the hydrogel, maintaining > 90% viability for up to 4 days. In a drug screening assay, diffusion of temozolomide and carmustine to hydrogel-encapsulated U87 cells from the perfusion solution is measured, and dose-response curves are generated, demonstrating utility as an in vitro mimic of the glioblastoma microenvironment.
Topics: Humans; Hydrogels; Lab-On-A-Chip Devices; Glioblastoma; Temozolomide; Carmustine; Siloxanes; Cell Culture Techniques; Polyethylene Glycols; Tumor Microenvironment
PubMed: 36273031
DOI: 10.1038/s41598-022-22439-y -
Cancer Medicine Aug 2014High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard therapy in patients with relapsed/refractory diffuse large B-cell lymphoma... (Meta-Analysis)
Meta-Analysis Review
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are chemosensitive. The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) is commonly used as a conditioning regimen. The addition of yttrium-90 ((90) Y)-ibritumomab tiuxetan (Zevalin(®)) to BEAM (Z-BEAM) is increasingly being used to improve outcomes and overcome refractory disease. We conducted a literature review and meta-analysis in order to evaluate the clinical effects of Z-BEAM followed by ASCT in patients with DLBCL. A literature search was conducted for randomized controlled trials and observational studies of Z-BEAM as a conditioning regimen for ASCT in adult patients with DLBCL. Extracted data included baseline patient demographics, overall response (ORR), complete response (CR), overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), median time to ANC and platelet engraftment, and rate of myelodysplastic syndrome. Mixed-effects models were used to determine estimates. Ten studies (N = 328) were included in the meta-analysis. The 2-year OS and PFS were 84.5% (n = 328) and 67.2% (n = 285), respectively. Outcomes were superior in patients with nontransformed lymphoma. Posttransplant, ORR and CR rates were 72.6% and 68.5%, respectively. The NRM rate was 6.3% and the incidence rate of myelodysplastic syndrome was 2.5%. Two-year OS was significantly associated with pretransplant ORR (P = 0.008, τ(2) = 0). There was no significant association between PFS and pretransplant response. Z-BEAM is safe and effective as a conditioning regimen in relapsed/refractory DLBCL.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Chemoradiotherapy; Cytarabine; Disease-Free Survival; Etoposide; Humans; Lymphoma, Large B-Cell, Diffuse; Melphalan; Radiopharmaceuticals; Treatment Outcome
PubMed: 24740968
DOI: 10.1002/cam4.247 -
Current Oncology Reports Mar 2022Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and... (Review)
Review
PURPOSE OF REVIEW
Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically.
RECENT FINDINGS
Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and several radiotherapy techniques. We critically appraise and compare these strategies in terms of their efficacy, toxicity, challenges and potential to prolong survival. Finally, we discuss the most promising strategies that could benefit future glioblastoma patients. There is biological rationale to suggest that early interventions could improve the outcome of glioblastoma patients and they should be investigated in future trials.
Topics: Adult; Antineoplastic Agents, Alkylating; Brain Neoplasms; Carmustine; Chemoradiotherapy; Glioblastoma; Humans; Tumor Microenvironment
PubMed: 35119629
DOI: 10.1007/s11912-021-01157-0 -
Aging Dec 2023Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors. The microenvironment of GBM is characterized by its highly immunosuppressive nature...
Glioblastoma multiforme (GBM) is one of the most common and aggressive brain tumors. The microenvironment of GBM is characterized by its highly immunosuppressive nature with infiltration of immunosuppressive cells and the expression levels of cytokines. Efferocytosis is a biological process in which phagocytes remove apoptotic cells and vesicles from tissues. Efferocytosis plays a noticeable function in the formation of immunosuppressive environment. This study aimed to develop an efferocytosis-related prognostic model for GBM. The bioinformatic methods were utilized to analyze the transcriptomic data of GBM and normal samples. Clinical and RNA-seq data were sourced from TCGA database comprising 167 tumor samples and 5 normal samples, and 167 tumor samples for which survival information was available. Transcriptomic data of 1034 normal samples were collected from the Genotype-Tissue Expression (GTEx) database as a control sample supplement to the TCGA database. In the end, 167 tumor samples and 1039 normal samples were obtained for transcriptome analysis. Efferocytosis-related differentially expressed genes (ERDEGs) were obtained by intersecting 7487 differentially expressed genes (DEGs) between GBM and normal samples along with 1189 hub genes. Functional enrichment analyses revealed that ERDEGs were mainly involved in cytokine-mediated immune responses. Moreover, 9 prognosis-related genes (PRGs) were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis, and a prognostic model was therefore developed. The nomogram combining age and risk score could effectively predict GBM patients' prognosis. GBM patients in the high-risk group had higher immune infiltration, invasion, epithelial-mesenchymal transition, angiogenesis scores and poorer tumor purity. In addition, the high-risk group exhibited higher half maximal inhibitory concentration (IC50) values for temozolomide, carmustine, and vincristine. Expression analysis indicated that PRGs were overexpressed in GBM cells. PDIA4 knockdown reduced efferocytosis . In summary, the proposed prognostic model for GBM based on efferocytosis-related genes exhibited a robust performance.
Topics: Humans; Glioblastoma; Prognosis; Efferocytosis; Carmustine; Temozolomide; Cytokines; Tumor Microenvironment
PubMed: 38159261
DOI: 10.18632/aging.205422 -
Bioscience Reports Aug 2018Carnosic acid (CA), a major polyphenolic diterpene present in , has been reported to have multiple functions, including antitumor activity. The MTT assay, BrdU...
Carnosic acid (CA), a major polyphenolic diterpene present in , 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 by Western blotting. B16F10 cell xenograft model 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 G/G 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) The present study study concluded that CA may be safe and useful as a novel chemotherapeutic agent.
Topics: Abietanes; Animals; Antineoplastic Agents, Alkylating; Antioxidants; Apoptosis; Carmustine; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Lomustine; Male; Melanoma, Experimental; Mice, Inbred C57BL
PubMed: 29789400
DOI: 10.1042/BSR20180005 -
Tumour Biology : the Journal of the... May 2017Resistance to conventional therapies and frequent recurrence are the major obstacles to the treatment of high-grade gliomas, including glioblastoma. Thus, the...
Resistance to conventional therapies and frequent recurrence are the major obstacles to the treatment of high-grade gliomas, including glioblastoma. Thus, the development of new therapeutic strategies to overcome these obstacles is necessary to improve the treatment outcomes. In this study, we found that verapamil, a pan-adenosine triphosphate-binding cassette transporter and L-type voltage-dependent calcium channel inhibitor, sensitized U87MG glioma cells to carmustine- and irradiation-induced senescence. Furthermore, our results indicated that verapamil treatment, in combination with carmustine and irradiation, rendered U87MG glioma cells and several patient-derived glioma stem cells more sensitive to therapy-induced senescence than individual or dual-combination treatments. When investigating the underlying mechanism, we found that verapamil treatment markedly decreased intracellular reactive oxygen species and calcium ion levels. Reactive oxygen species reduction with N-acetylcysteine, a reactive oxygen species scavenger, rendered U87MG glioma cells more sensitive to carmustine and irradiation whereas the protein kinase C agonist, phorbol 12-myristate 13-acetate, mitigated the effects of carmustine and irradiation. Taken together, our results indicate that verapamil may be a potent therapeutic sensitizer for increasing the effectiveness of glioblastoma treatment.
Topics: Antineoplastic Combined Chemotherapy Protocols; Calcium; Calcium Channels, L-Type; Carmustine; Cell Line, Tumor; Cellular Senescence; Combined Modality Therapy; Glioma; Humans; Neoplasm Recurrence, Local; Reactive Oxygen Species; Verapamil
PubMed: 28459217
DOI: 10.1177/1010428317692244 -
Leukemia & Lymphoma Mar 2022Relapsed/refractory Primary Central Nervous System Lymphoma (R/R PCNSL) has a poor prognosis with no established preferred treatment. We report the efficacy and toxicity...
Rituximab, Methotrexate, Carmustine, Etoposide, and Prednisone (RMBVP) for the treatment of relapsed/refractory primary central nervous system lymphoma: a retrospective single-center study.
Relapsed/refractory Primary Central Nervous System Lymphoma (R/R PCNSL) has a poor prognosis with no established preferred treatment. We report the efficacy and toxicity of a combination chemotherapy regimen: methotrexate, carmustine, etoposide, and prednisone with or without rituximab (RMBVP). This retrospective study included thirty patients who received a median of two 28-day cycles (0.5-5). The median age was 66 years (23-81); median KPS was 70 (30-90); 14 (46.7%) were women. Patients received a median of 2 prior lines of therapy and all received prior methotrexate. Of 29 evaluable patients, the overall response rate was 73.3% ( = 22). Median progression-free survival (PFS) was 15.6 months. Patients who recurred or progressed <12 months since last chemotherapy had a shorter median PFS (7.6 vs 37.6 months). Toxicity was moderate with 20% rates of severe myelosuppression. RMBVP is a tolerable treatment option for R/R PCNSL, with favorable response rates in those with recurrent disease.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Central Nervous System; Central Nervous System Neoplasms; Etoposide; Female; Humans; Lymphoma, Non-Hodgkin; Methotrexate; Neoplasm Recurrence, Local; Prednisone; Retrospective Studies; Rituximab
PubMed: 34758711
DOI: 10.1080/10428194.2021.1998481 -
Indian Journal of Cancer 2011Glioblastoma is a rapidly progressive and extremely fatal form of brain tumor with poor prognosis. It is the most common type of primary brain tumor. Even with the most... (Review)
Review
Glioblastoma is a rapidly progressive and extremely fatal form of brain tumor with poor prognosis. It is the most common type of primary brain tumor. Even with the most aggressive conventional treatment that comprises surgery followed by radiotherapy and chemotherapy, most patients die within a year of diagnosis. Developments in molecular and cell biology have led to better understanding of tumor development, leading to novel treatment strategies including biological therapy and immunotherapy to combat the deadly disease. Targeted drug delivery strategies to circumvent the blood-brain barrier have shown efficiency in clinical trials. Gliadel wafer is a new approach to the treatment of glioblastoma, which involves controlled release delivery of carmustine from biodegradable polymer wafers. It has shown promising results and provides a silver lining for glioblastoma patients.
Topics: Antineoplastic Agents, Alkylating; Brain Neoplasms; Carmustine; Delayed-Action Preparations; Humans
PubMed: 21330749
DOI: 10.4103/0019-509X.76623 -
Cytotherapy May 2024The combination therapy of autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell (CART) therapy has been employed to improve...
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...
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.
Topics: Humans; Male; Carmustine; Melphalan; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Middle Aged; Adult; Transplantation, Autologous; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Vidarabine; Prognosis; Aged; Lymphoma, B-Cell; Podophyllotoxin; Immunotherapy, Adoptive; Young Adult; Combined Modality Therapy; Transplantation Conditioning; Receptors, Chimeric Antigen
PubMed: 38385909
DOI: 10.1016/j.jcyt.2024.01.012 -
Biomaterials Nov 1990Brain tumours are difficult to treat by conventional methods. A biodegradable polymer, poly-[bis(p-carboxyphenoxy)propane sebacic acid] with a nitrosourea, carmustine,... (Review)
Review
Brain tumours are difficult to treat by conventional methods. A biodegradable polymer, poly-[bis(p-carboxyphenoxy)propane sebacic acid] with a nitrosourea, carmustine, has been demonstrated to be biocompatible in the brains of experimental animals and to release drugs in a predictable sustained manner. Carmustine impregnated in polymers appears to be more effective than when delivered by standard methods. A Phase I clinical study has demonstrated the safety of this approach in treating brain tumours and a Phase III placebo-controlled study is currently underway. Other applications of the polymer in the treatment of brain diseases are discussed.
Topics: Animals; Biocompatible Materials; Biodegradation, Environmental; Brain Neoplasms; Carmustine; Delayed-Action Preparations; Dexamethasone; Drug Implants; Humans; Polymers
PubMed: 2090306
DOI: 10.1016/0142-9612(90)90030-t