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1.
BMJ Open Ophthalmol ; 9(1)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38960415

RESUMO

BACKGROUND: To investigate if there are improvements in trabeculectomy outcomes supporting filtration bleb formation caused by Rho-associated protein kinase (ROCK) inhibitors. METHODS: This prospective, multicentre, randomised, open-label clinical study examined open-angle glaucoma patients who underwent trabeculectomy or trabeculectomy combined with cataract surgery followed by 3-month postoperative ripasudil treatments. After randomly allocating patients to ripasudil-ROCK inhibitor (ripasudil) or without ripasudil (non-ripasudil) groups. Mean intraocular pressure (IOP) changes, success rate, and number of eyedrops were compared for both groups. RESULTS: A total of 17 and 15 subjects dropped out in the ripasudil group and non-ripasudil group, respectively. At baseline, the mean IOP was 16.8±5.0 mm Hg in the ripasudil group (38 patients) and 16.2±4.4 in the non-ripasudil group (52 patients). The IOP decreased to 11.4±3.2 mm Hg, 10.9±3.9 mm Hg and 10.6±3.5 mm Hg at 12, 24 and 36 months in the ripasudil group, while it decreased to 11.2±4.1 mm Hg, 10.5±3.1 mm Hg and 10.9±3.2 mm Hg at 12, 24 and 36 months in the non-ripasudil group, respectively. There was a significant decrease in the number of IOP-lowering medications after trabeculectomy in the ripasudil group versus the non-ripasudil group at 24 (p=0.010) and 36 months (p=0.016). There was no statistically significant difference between the groups for the 3-year cumulative probability of success. CONCLUSION: Although ripasudil application did not increase the primary trabeculectomy success rate, it did reduce IOP-lowering medications after trabeculectomy with mitomycin C.


Assuntos
Glaucoma de Ângulo Aberto , Pressão Intraocular , Isoquinolinas , Mitomicina , Sulfonamidas , Trabeculectomia , Humanos , Trabeculectomia/métodos , Masculino , Pressão Intraocular/efeitos dos fármacos , Estudos Prospectivos , Feminino , Glaucoma de Ângulo Aberto/cirurgia , Glaucoma de Ângulo Aberto/tratamento farmacológico , Isoquinolinas/uso terapêutico , Isoquinolinas/administração & dosagem , Idoso , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Mitomicina/uso terapêutico , Mitomicina/administração & dosagem , Pessoa de Meia-Idade , Quinases Associadas a rho/antagonistas & inibidores , Resultado do Tratamento , Alquilantes/administração & dosagem , Alquilantes/uso terapêutico
2.
Nagoya J Med Sci ; 86(2): 304-313, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38962412

RESUMO

Radiotherapy combined with temozolomide (TMZ+RT) is the primary treatment for high-grade glioma. TMZ is classified as a moderate emetic risk agent and, thus, supportive care for nausea and vomiting is important. In Nagoya University Hospital, all patients are treated with a 5-hydroxy-tryptamine 3 receptor antagonist (5-HT3RA) for the first 3 days. The daily administration of 5-HT3RA is resumed after the 4th day based on the condition of patients during TMZ+RT. Therefore, the present study investigated risk factors for nausea and vomiting in patients requiring the daily administration of 5-HT3RA. Patients with high-grade glioma who received TMZ+RT between January 2014 and December 2019 at our hospital were included. Patients were divided into two groups: a control group (patients who did not resume 5-HT3RA) and resuming 5-HT3RA group (patients who resumed 5-HT3RA after the 4th day), and both groups were compared to identify risk factors for nausea and vomiting during TMZ+RT. There were 78 patients in the control group (68%) and 36 in the resuming 5-HT3RA group (32%). A multivariate analysis of patient backgrounds in the two groups identified age <18 years, PS 2 or more, and occipital lobe tumors as risk factors for nausea and vomiting. Nausea and vomiting were attenuated in 30 patients (83%) in the resuming 5-HT3RA group following the resumption of 5-HT3RA. The results obtained highlight the importance of extracting patients with these risk factors before the initiation of therapy and the early resumption or daily administration of 5-HT3RA according to the condition of each patient.


Assuntos
Glioma , Náusea , Antagonistas do Receptor 5-HT3 de Serotonina , Temozolomida , Vômito , Humanos , Temozolomida/uso terapêutico , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos , Masculino , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Antagonistas do Receptor 5-HT3 de Serotonina/administração & dosagem , Feminino , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Pessoa de Meia-Idade , Glioma/tratamento farmacológico , Glioma/radioterapia , Fatores de Risco , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Adulto , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos
3.
Clin Transl Sci ; 17(7): e13866, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38965809

RESUMO

Rising cure rates in pediatric cancer patients warrants an increased attention toward the long-term consequences of the diagnosis and treatment in survivors. Chemotherapeutic agents can be gonadotoxic, rendering them at risk for infertility post-survival. While semen cryopreservation is an option that can be provided for most (post)pubertal boys before treatment, this is unfortunately not an option prepubertal in age, simply due to the lack of spermatogenesis. Over the last couple of years, studies have thus focused on better understanding the testis niche in response to various chemotherapeutic agents that are commonly administered and their direct and indirect impact on the germ cell populations. These are generally compounds that have a high risk of infertility and have been classified into risk categories in curated fertility guidelines. However, with it comes the lack of evidence and the challenge of using informative models and conditions most reflective of the physiological scenario, in short, the appropriate study designs for clinically relevant outcomes. Besides, the exact mechanism(s) of action for many of these "risk" compounds as well as other agents is unclear. Understanding their behavior and effect on the testis niche will pave the way for incorporating new strategies to ultimately combat infertility. Of the various drug classes, alkylating agents pose the highest risk of gonadotoxicity as per previously established studies as well as risk stratification guidelines. Therefore, this review will summarize the findings in the field of male fertility concerning gonadotoxicity of akylating agents as a result of chemotherapy exposure.


Assuntos
Antineoplásicos Alquilantes , Testículo , Humanos , Masculino , Testículo/efeitos dos fármacos , Criança , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/etiologia , Infertilidade Masculina/diagnóstico , Animais , Espermatogênese/efeitos dos fármacos , Espermatogênese/efeitos da radiação , Neoplasias/tratamento farmacológico , Puberdade/efeitos dos fármacos , Puberdade/fisiologia , Alquilantes/efeitos adversos , Alquilantes/administração & dosagem
4.
BMC Cancer ; 24(1): 747, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898388

RESUMO

BACKGROUND: The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. PATIENTS AND METHODS: The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. RESULTS: The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3-4 non-haematological toxicities. CONCLUSIONS: 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.


Assuntos
Neoplasias Ósseas , Ifosfamida , Recidiva Local de Neoplasia , Osteossarcoma , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Ifosfamida/uso terapêutico , Masculino , Feminino , Estudos Retrospectivos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Adulto , Adolescente , Adulto Jovem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Pessoa de Meia-Idade , Criança , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Gradação de Tumores , Resultado do Tratamento
5.
Med Oncol ; 41(7): 177, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38884819

RESUMO

Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.


Assuntos
Neoplasias do Sistema Nervoso Central , Injeções Espinhais , Tiotepa , Humanos , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/secundário , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/secundário
6.
J Cell Sci ; 137(12)2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38940347

RESUMO

Some chemotherapy drugs modulate the formation of stress granules (SGs), which are RNA-containing cytoplasmic foci contributing to stress response pathways. How SGs mechanistically contribute to pro-survival or pro-apoptotic functions must be better defined. The chemotherapy drug lomustine promotes SG formation by activating the stress-sensing eIF2α kinase HRI (encoded by the EIF2AK1 gene). Here, we applied a DNA microarray-based transcriptome analysis to determine the genes modulated by lomustine-induced stress and suggest roles for SGs in this process. We found that the expression of the pro-apoptotic EGR1 gene was specifically regulated in cells upon lomustine treatment. The appearance of EGR1-encoding mRNA in SGs correlated with a decrease in EGR1 mRNA translation. Specifically, EGR1 mRNA was sequestered to SGs upon lomustine treatment, probably preventing its ribosome translation and consequently limiting the degree of apoptosis. Our data support the model where SGs can selectively sequester specific mRNAs in a stress-specific manner, modulate their availability for translation, and thus determine the fate of a stressed cell.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce , Lomustina , RNA Mensageiro , Humanos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , Lomustina/farmacologia , Grânulos de Estresse/metabolismo , Grânulos de Estresse/genética , Apoptose/efeitos dos fármacos , Antineoplásicos Alquilantes/farmacologia
7.
DNA Repair (Amst) ; 140: 103700, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38897003

RESUMO

Mutations in isocitrate dehydrogenase isoform 1 (IDH1) are primarily found in secondary glioblastoma (GBM) and low-grade glioma but are rare in primary GBM. The standard treatment for GBM includes radiation combined with temozolomide, an alkylating agent. Fortunately, IDH1 mutant gliomas are sensitive to this treatment, resulting in a more favorable prognosis. However, it's estimated that up to 75 % of IDH1 mutant gliomas will progress to WHO grade IV over time and develop resistance to alkylating agents. Therefore, understanding the mechanism(s) by which IDH1 mutant gliomas confer sensitivity to alkylating agents is crucial for developing targeted chemotherapeutic approaches. The base excision repair (BER) pathway is responsible for repairing most base damage induced by alkylating agents. Defects in this pathway can lead to hypersensitivity to these agents due to unresolved DNA damage. The coordinated assembly and disassembly of BER protein complexes are essential for cell survival and for maintaining genomic integrity following alkylating agent exposure. These complexes rely on poly-ADP-ribose formation, an NAD+-dependent post-translational modification synthesized by PARP1 and PARP2 during the BER process. At the lesion site, poly-ADP-ribose facilitates the recruitment of XRCC1. This scaffold protein helps assemble BER proteins like DNA polymerase beta (Polß), a bifunctional DNA polymerase containing both DNA synthesis and 5'-deoxyribose-phosphate lyase (5'dRP lyase) activity. Here, we confirm that IDH1 mutant glioma cells have defective NAD+ metabolism, but still produce sufficient nuclear NAD+ for robust PARP1 activation and BER complex formation in response to DNA damage. However, the overproduction of 2-hydroxyglutarate, an oncometabolite produced by the IDH1 R132H mutant protein, suppresses BER capacity by reducing Polß protein levels. This defines a novel mechanism by which the IDH1 mutation in gliomas confers cellular sensitivity to alkylating agents and to inhibitors of the poly-ADP-ribose glycohydrolase, PARG.


Assuntos
DNA Polimerase beta , Glutaratos , Isocitrato Desidrogenase , DNA Polimerase beta/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Isocitrato Desidrogenase/genética , Glutaratos/metabolismo , Linhagem Celular Tumoral , Reparo do DNA , Antineoplásicos Alquilantes/farmacologia , Temozolomida/farmacologia , Mutação , Glioma/metabolismo , Glioma/genética , Glioma/tratamento farmacológico , Alquilantes/farmacologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Dano ao DNA
8.
Trials ; 25(1): 366, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849943

RESUMO

BACKGROUND: Chemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known. METHODS: EORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0-2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union's Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028. DISCUSSION: EORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023.


Assuntos
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Progressão da Doença , Glioblastoma , Lomustina , Estudos Multicêntricos como Assunto , Intervalo Livre de Progressão , Glioblastoma/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Glioblastoma/radioterapia , Glioblastoma/terapia , Humanos , Lomustina/administração & dosagem , Lomustina/uso terapêutico , Lomustina/efeitos adversos , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Antineoplásicos Alquilantes/uso terapêutico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Quimiorradioterapia/métodos , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Pragmáticos como Assunto , Fatores de Tempo
9.
Sci Rep ; 14(1): 14341, 2024 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-38906916

RESUMO

Glioblastoma (GBM) is a highly aggressive and deadly brain cancer. Temozolomide (TMZ) is the standard chemotherapeutic agent for GBM, but the majority of patients experience recurrence and invasion of tumor cells. We investigated whether TMZ treatment of GBM cells regulates matrix metalloproteinases (MMPs), which have the main function to promote tumor cell invasion. TMZ effectively killed GL261, U343, and U87MG cells at a concentration of 500 µM, and surviving cells upregulated MMP9 expression and its activity but not those of MMP2. TMZ also elevated levels of MMP9 mRNA and MMP9 promoter activity. Subcutaneous graft tumors survived from TMZ treatment also exhibited increased expression of MMP9 and enhanced gelatinolytic activity. TMZ-mediated MMP9 upregulation was specifically mediated through the phosphorylation of p38 and JNK. This then stimulates AP-1 activity through the upregulation of c-Fos and c-Jun. Inhibition of the p38, JNK, or both pathways counteracted the TMZ-induced upregulation of MMP9 and AP-1. This study proposes a potential adverse effect of TMZ treatment for GBM: upregulation of MMP9 expression potentially associated with increased invasion and poor prognosis. This study also provides valuable insights into the molecular mechanisms by which TMZ treatment leads to increased MMP9 expression in GBM cells.


Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma , Metaloproteinase 9 da Matriz , Temozolomida , Proteínas Quinases p38 Ativadas por Mitógeno , Temozolomida/farmacologia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/genética , Glioblastoma/patologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Humanos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Antineoplásicos Alquilantes/farmacologia , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fator de Transcrição AP-1/metabolismo , Regulação para Cima/efeitos dos fármacos , Camundongos
10.
Drug Des Devel Ther ; 18: 2021-2032, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38863768

RESUMO

In the era of single and combination maintenance therapies as well as platinum and Poly (ADP-ribose) polymerase inhibitors (PARPi) resistance, the choice of subsequent treatments following first-line platinum-based chemotherapy in recurrent ovarian cancer (ROC) patients has become increasingly complex. Within the ovarian cancer treatment algorithm, particularly in the emerging context of PARPi resistance, the role of trabectedin, in combination with pegylated liposomal doxorubicin (PLD) still preserves its significance. This paper offers valuable insights into the multifaceted role and mechanism of action of trabectedin in ROC. The main results of clinical trials and studies involving trabectedin/PLD, along with hints of Breast Cancer genes (BRCA)-mutated and BRCAness phenotype cases, are critically discussed. Moreover, this review provides and contextualizes potential scenarios of administering trabectedin in combination with PLD in ROC, according to established guidelines and beyond.


Assuntos
Neoplasias Ovarianas , Trabectedina , Trabectedina/uso terapêutico , Trabectedina/farmacologia , Trabectedina/administração & dosagem , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Feminino , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Tetra-Hidroisoquinolinas/farmacologia , Tetra-Hidroisoquinolinas/uso terapêutico , Tetra-Hidroisoquinolinas/administração & dosagem , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Dioxóis/administração & dosagem , Doxorrubicina/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
13.
J Neurooncol ; 168(3): 393-404, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38780714

RESUMO

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.


Assuntos
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Carmustina , Glioma , Pontuação de Propensão , Humanos , Masculino , Feminino , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Carmustina/uso terapêutico , Glioma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Encefálicas/cirurgia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/administração & dosagem , Adulto , Estudos Retrospectivos , Prognóstico , Estudos de Coortes , Idoso , Implantes de Medicamento , Taxa de Sobrevida , Seguimentos
14.
Anticancer Res ; 44(6): 2359-2367, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38821601

RESUMO

BACKGROUND/AIM: The alkylating agent trabectedin, which binds the minor groove of DNA, is second-line therapy for soft-tissue sarcoma but has only moderate efficacy. The aim of the present study was to determine the synergistic efficacy of recombinant methioninase (rMETase) and trabectedin on fibrosarcoma cells in vitro, compared with normal fibroblasts. MATERIALS AND METHODS: HT1080 human fibrosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm and Hs27 normal human fibroblasts, were used. Each cell line was cultured in vitro and divided into four groups: no-treatment control; trabectedin treated; rMETase treated; and trabectedin plus rMETase treated. The dual-color HT1080 cells were used to quantitate nuclear fragmentation in each treatment group. RESULTS: The combination of rMETase and trabectedin was highly synergistic to decrease HT1080 cell viability. In contrast, there was no synergy on Hs27 cells. Moreover, nuclear fragmentation occurred synergistically with the combination of trabectedin and rMETase on dual-color HT1080 cells. CONCLUSION: The combination treatment of trabectedin plus rMETase was highly synergistic on fibrosarcoma cells in vitro suggesting that the combination can improve the outcome of trabectedin alone in future clinical studies. The lack of synergy of rMETase and trabectedin on normal fibroblasts suggests the combination is not toxic to normal cells. Synergy of the two drugs may be due to the high rate of nuclear fragmentation on treated HT1080 cells, and the late-S/G2 cell-cycle block of cancer cells by rMETase, which is a target for trabectedin. The results of the present study suggest the future clinical potential of the combination of rMETase and trabectedin for soft-tissue sarcoma.


Assuntos
Liases de Carbono-Enxofre , Sobrevivência Celular , Dioxóis , Sinergismo Farmacológico , Fibroblastos , Fibrossarcoma , Tetra-Hidroisoquinolinas , Trabectedina , Humanos , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/patologia , Fibrossarcoma/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Trabectedina/farmacologia , Liases de Carbono-Enxofre/farmacologia , Liases de Carbono-Enxofre/administração & dosagem , Tetra-Hidroisoquinolinas/farmacologia , Dioxóis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Linhagem Celular Tumoral , Antineoplásicos Alquilantes/farmacologia , Núcleo Celular/metabolismo , Núcleo Celular/efeitos dos fármacos
15.
Ann Surg Oncol ; 31(8): 5340-5351, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38704501

RESUMO

BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).


Assuntos
Antineoplásicos Alquilantes , Neoplasias Hepáticas , Melanoma , Melfalan , Neoplasias Uveais , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/secundário , Melanoma/mortalidade , Melfalan/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/patologia , Neoplasias Uveais/mortalidade , Idoso , Adulto , Taxa de Sobrevida , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Seguimentos , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/uso terapêutico , Prognóstico , Idoso de 80 Anos ou mais , Sistemas de Liberação de Medicamentos
17.
Am J Hematol ; 99(8): 1540-1549, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38742955

RESUMO

One key aspect of allogeneic hematopoietic cell transplantation (HCT) is pretransplant conditioning, balancing risk for relapse versus non-relapse mortality. Conditioning regimens with different alkylators at different doses can influence outcome, but data are missing for myelofibrosis, a challenging cohort of patients usually presenting at older age and with comorbidities. We evaluated in a multicenter retrospective study the comparative efficacy and safety of busulfan versus treosulfan in combination with fludarabine for myelofibrosis patients undergoing HCT. This study included 1115 patients (busulfan, n = 902; treosulfan, n = 213) receiving first HCT between 2005 and 2021. Patients were generally balanced for key patient characteristics. Overall survival at 4 years was 62% for the busulfan group versus 58% for the treosulfan group (p = .22). Impact on outcome was dose-dependent. Overall survival was 65% (95% CI, 61%-69%) for reduced intensity busulfan versus 69% (95% CI, 54%-84%) for reduced intensity treosulfan, 53% (95% CI, 44%-63%) for higher intensity busulfan, and 55% (95% CI, 46%-63%) for higher intensity treosulfan. Incidence of relapse was similar across intensity groups. In multivariable analysis, the hazard for death (with reduced intensity busulfan as reference) was 0.88 (95% CI, 0.39-2.01) for reduced intensity treosulfan (p = .77), 1.42 (95% CI, 0.96-2.10) for higher intensity busulfan (0.08), and 1.61 (95% CI, 1.14-2.26) for higher intensity treosulfan (p = .006). In terms of non-relapse mortality, comparison was not significantly different, while the hazard ratio for higher intensity treosulfan was 1.48 (95% CI, 0.98-2.23; p = .06). Here, we showed comparable outcomes and improved survival in myelofibrosis undergoing HCT with reduced intensity busulfan or treosulfan.


Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Condicionamento Pré-Transplante , Vidarabina , Bussulfano/análogos & derivados , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Humanos , Mielofibrose Primária/terapia , Mielofibrose Primária/mortalidade , Mielofibrose Primária/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino , Condicionamento Pré-Transplante/métodos , Estudos Retrospectivos , Idoso , Adulto , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/administração & dosagem , Adulto Jovem
18.
J Nanobiotechnology ; 22(1): 264, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760771

RESUMO

Glioblastoma (GBM) is the most aggressive primary brain tumor with low survival rate. Currently, temozolomide (TMZ) is the first-line drug for GBM treatment of which efficacy is unfortunately hindered by short circulation time and drug resistance associated to hypoxia and redox tumor microenvironment. Herein, a dual-targeted and multi-responsive nanoplatform is developed by loading TMZ in hollow manganese dioxide nanoparticles functionalized by polydopamine and targeting ligands RAP12 for photothermal and receptor-mediated dual-targeted delivery, respectively. After accumulated in GBM tumor site, the nanoplatform could respond to tumor microenvironment and simultaneously release manganese ion (Mn2+), oxygen (O2) and TMZ. The hypoxia alleviation via O2 production, the redox balance disruption via glutathione consumption and the reactive oxygen species generation, together would down-regulate the expression of O6-methylguanine-DNA methyltransferase under TMZ medication, which is considered as the key to drug resistance. These strategies could synergistically alleviate hypoxia microenvironment and overcome TMZ resistance, further enhancing the anti-tumor effect of chemotherapy/chemodynamic therapy against GBM. Additionally, the released Mn2+ could also be utilized as a magnetic resonance imaging contrast agent for monitoring treatment efficiency. Our study demonstrated that this nanoplatform provides an alternative approach to the challenges including low delivery efficiency and drug resistance of chemotherapeutics, which eventually appears to be a potential avenue in GBM treatment.


Assuntos
Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Compostos de Manganês , Nanopartículas , Óxidos , Temozolomida , Microambiente Tumoral , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Linhagem Celular Tumoral , Animais , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Nanopartículas/química , Neoplasias Encefálicas/tratamento farmacológico , Óxidos/química , Óxidos/farmacologia , Camundongos , Sistemas de Liberação de Medicamentos/métodos , Indóis/química , Indóis/farmacologia , Polímeros/química , Camundongos Nus , Camundongos Endogâmicos BALB C , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
19.
Cell Death Dis ; 15(5): 318, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710703

RESUMO

Glioblastoma stem cells (GSCs) play a key role in glioblastoma (GBM) resistance to temozolomide (TMZ) chemotherapy. With the increase in research on the tumour microenvironment, exosomes secreted by GSCs have become a new focus in GBM research. However, the molecular mechanism by which GSCs affect drug resistance in GBM cells via exosomes remains unclear. Using bioinformatics analysis, we identified the specific expression of ABCB4 in GSCs. Subsequently, we established GSC cell lines and used ultracentrifugation to extract secreted exosomes. We conducted in vitro and in vivo investigations to validate the promoting effect of ABCB4 and ABCB4-containing exosomes on TMZ resistance. Finally, to identify the transcription factors regulating the transcription of ABCB4, we performed luciferase assays and chromatin immunoprecipitation-quantitative PCR. Our results indicated that ABCB4 is highly expressed in GSCs. Moreover, high expression of ABCB4 promoted the resistance of GSCs to TMZ. Our study found that GSCs can also transmit their highly expressed ABCB4 to differentiated glioma cells (DGCs) through exosomes, leading to high expression of ABCB4 in these cells and promoting their resistance to TMZ. Mechanistic studies have shown that the overexpression of ABCB4 in GSCs is mediated by the transcription factor ATF3. In conclusion, our results indicate that GSCs can confer resistance to TMZ in GBM by transmitting ABCB4, which is transcribed by ATF3, through exosomes. This mechanism may lead to drug resistance and recurrence of GBM. These findings contribute to a deeper understanding of the mechanisms underlying drug resistance in GBM and provide novel insights into its treatment.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Fator 3 Ativador da Transcrição , Neoplasias Encefálicas , Resistencia a Medicamentos Antineoplásicos , Exossomos , Glioblastoma , Células-Tronco Neoplásicas , Temozolomida , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Glioblastoma/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Exossomos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Fator 3 Ativador da Transcrição/metabolismo , Fator 3 Ativador da Transcrição/genética , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Camundongos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Nus
20.
Front Immunol ; 15: 1369972, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38690285

RESUMO

Background: Temozolomide (TMZ) is a key component in the treatment of gliomas. Hypermutation induced by TMZ can be encountered in routine clinical practice, and its significance is progressively gaining recognition. However, the relationship between TMZ-induced hypermutation and the immunologic response remains controversial. Case presentation: We present the case of a 38-year-old male patient who underwent five surgeries for glioma. Initially diagnosed with IDH-mutant astrocytoma (WHO grade 2) during the first two surgeries, the disease progressed to grade 4 in subsequent interventions. Prior to the fourth surgery, the patient received 3 cycles of standard TMZ chemotherapy and 9 cycles of dose-dense TMZ regimens. Genomic and immunologic analyses of the tumor tissue obtained during the fourth surgery revealed a relatively favorable immune microenvironment, as indicated by an immunophenoscore of 5, suggesting potential benefits from immunotherapy. Consequently, the patient underwent low-dose irradiation combined with immunoadjuvant treatment. After completing 4 cycles of immunotherapy, the tumor significantly shrank, resulting in a partial response. However, after a 6-month duration of response, the patient experienced disease progression. Subsequent analysis of the tumor tissue obtained during the fifth surgery revealed the occurrence of hypermutation, with mutation signature analysis attributing TMZ treatment as the primary cause. Unfortunately, the patient succumbed shortly thereafter, with a survival period of 126 months. Conclusion: Patients subjected to a prolonged regimen of TMZ treatment may exhibit heightened vulnerability to hypermutation. This hypermutation induced by TMZ holds the potential to function as an indicator associated with unfavorable response to immunotherapy in gliomas.


Assuntos
Antineoplásicos Alquilantes , Neoplasias Encefálicas , Glioma , Mutação , Temozolomida , Humanos , Temozolomida/uso terapêutico , Masculino , Adulto , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Glioma/genética , Glioma/terapia , Glioma/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Imunoterapia/métodos , Evolução Fatal , Microambiente Tumoral/imunologia
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