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1.
Cancer Sci ; 113(9): 3055-3070, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35657686

RESUMO

5-Fluorouracil (5-FU) is widely used in gastric cancer treatment, yet 5-FU resistance remains an important clinical challenge. We established a model based on five long noncoding RNAs (lncRNA) to effectively assess the prognosis of gastric cancer patients; among them, lncRNA OVAAL was markedly upregulated in gastric cancer and associated with poor prognosis and 5-FU resistance. In vitro and in vivo assays confirmed that OVAAL promoted proliferation and 5-FU resistance of gastric cancer cells. Mechanistically, OVAAL bound with pyruvate carboxylase (PC) and stabilized PC from HSC70/CHIP-mediated ubiquitination and degradation. OVAAL knockdown reduced intracellular levels of oxaloacetate and aspartate, and the subsequent pyrimidine synthesis, which could be rescued by PC overexpression. Moreover, OVAAL knockdown increased sensitivity to 5-FU treatment, which could be reversed by PC overexpression or repletion of oxaloacetate, aspartate, or uridine. OVAAL overexpression enhanced pyrimidine synthesis to promote proliferation and 5-FU resistance of gastric cancer cells, which could be abolished by PC knockdown. Thus, OVAAL promoted gastric cancer cell proliferation and induced 5-FU resistance by enhancing pyrimidine biosynthesis to antagonize 5-FU induced thymidylate synthase dysfunction. Targeting OVAAL-mediated nucleotide metabolic reprograming would be a promising strategy to overcome chemoresistance in gastric cancer.


Assuntos
RNA Longo não Codificante , Neoplasias Gástricas , Ácido Aspártico/farmacologia , Ácido Aspártico/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Nucleotídeos/farmacologia , Nucleotídeos/uso terapêutico , Oxaloacetatos/farmacologia , Oxaloacetatos/uso terapêutico , Piruvato Carboxilase/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo
2.
Cell Metab ; 34(6): 919-936.e8, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35675800

RESUMO

Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.


Assuntos
ATP Citrato (pro-S)-Liase , Dislipidemias , Hepatopatia Gordurosa não Alcoólica , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , Acetil-CoA Carboxilase , Animais , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Fígado , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Oxaloacetatos/metabolismo , Triglicerídeos
3.
Int J Mol Sci ; 23(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35682716

RESUMO

Gastric cancer (GC) is one of the most common cancers and a leading cause of cancer deaths around the world. Chemotherapy is one of the most effective treatments for cancer patients, and has remarkably enhanced survival rates. However, it has many side effects. Recently, microRNAs (miRNAs) have been intensively studied as potential biomarkers for cancer diagnosis and treatment monitoring. However, definitive biomarkers in chemotherapy-induced peripheral neuropathy (CIPN) are still lacking. The aim of this study was to identify the factors significant for neurological adverse events in GC patients receiving XELOX (oxaliplatin and capecitabine) chemotherapy. The results show that XELOX chemotherapy induces changes in the expression of hsa-miR-200c-3p, hsa-miR-885-5p, and hsa-miR-378f. Validation by qRT-PCR demonstrated that hsa-miR-378f was significantly downregulated in CIPN. Hsa-miR-378f was identified as showing a statistically significant correlation in GC patients receiving XELOX chemotherapy according to the analysis of differentially expressed (DE) miRNAs. Furthermore, 34 potential target genes were predicted using a web-based database for miRNA target prognostication and functional annotations. The identified genes are related to the peptidyl-serine phosphorylation and regulation of alternative mRNA splicing with enrichment in the gastric cancer, neurotrophin, MAPK, and AMPK signaling pathways. Collectively, these results provide information useful for developing promising strategies for the treatment of XELOX-chemotherapy-induced peripheral neuropathy.


Assuntos
Antineoplásicos , MicroRNA Circulante , MicroRNAs , Doenças do Sistema Nervoso Periférico , Neoplasias Gástricas , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores , Capecitabina/efeitos adversos , MicroRNA Circulante/genética , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Oxaloacetatos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
4.
Mol Metab ; 62: 101516, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35598879

RESUMO

OBJECTIVE: The prostate is metabolically unique: it produces high levels of citrate for secretion via a truncated tricarboxylic acid (TCA) cycle to maintain male fertility. In prostate cancer (PCa), this phenotype is reprogrammed, making it an interesting therapeutic target. However, how the truncated prostate TCA cycle works is still not completely understood. METHODS: We optimized targeted metabolomics in mouse and human organoid models in ex vivo primary culture. We then used stable isotope tracer analyses to identify the pathways that fuel citrate synthesis. RESULTS: First, mouse and human organoids were shown to recapitulate the unique citrate-secretory program of the prostate, thus representing a novel model that reproduces this unusual metabolic profile. Using stable isotope tracer analysis, several key nutrients were shown to allow the completion of the prostate TCA cycle, revealing a much more complex metabolic profile than originally anticipated. Indeed, along with the known pathway of aspartate replenishing oxaloacetate, glutamine was shown to fuel citrate synthesis through both glutaminolysis and reductive carboxylation in a GLS1-dependent manner. In human organoids, aspartate entered the TCA cycle at the malate entry point, upstream of oxaloacetate. Our results demonstrate that the citrate-secretory phenotype of prostate organoids is supported by the known aspartate-oxaloacetate-citrate pathway, but also by at least three additional pathways: glutaminolysis, reductive carboxylation, and aspartate-malate conversion. CONCLUSIONS: Our results add a significant new dimension to the prostate citrate-secretory phenotype, with at least four distinct pathways being involved in citrate synthesis. Better understanding this distinctive citrate metabolic program will have applications in both male fertility as well as in the development of novel targeted anti-metabolic therapies for PCa.


Assuntos
Ciclo do Ácido Cítrico , Malatos , Animais , Ácido Aspártico/metabolismo , Citratos/metabolismo , Ácido Cítrico/metabolismo , Humanos , Malatos/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Oxaloacetatos/metabolismo , Próstata/metabolismo
5.
Yeast ; 39(5): 337-347, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35384037

RESUMO

The yeast Komagataella phaffii (a.k.a. Pichia pastoris) harbours a unique glutamate utilization pathway in which the cytosolic enzymes glutamate dehydrogenase 2 (GDH2), aspartate aminotransferase 2 (AAT2) and phosphoenolpyruvate carboxykinase (PEPCK) catalyze the sequential conversion of glutamate to α-ketoglutarate, oxaloacetate and phosphoenolpyruvate respectively. GDH2 and PEPCK are essential for glutamate catabolism. Their synthesis is induced by autophagy during carbon starvation and are essential for cell survival. Here, we demonstrate that GDH2 and PEPCK reciprocally regulate each other's protein levels during glutamate catabolism such that GDH2 is downregulated in Δpepck and PEPCK is downregulated in Δgdh2. We further demonstrate that sequential conversion of glutamate to α-ketoglutarate and oxaloacetate by GDH2 and AAT2, respectively, is essential for PEPCK synthesis in cells metabolizing glutamate. Our studies indicate that translation of GDH2 mRNA is induced by glutamate while oxaloacetate derived from glutamate is likely to be the inducer of PEPCK mRNA translation during glutamate catabolism. Thus, GDH2- and PEPCK-catalyzed reactions are essential for ATP generation and gluconeogenesis respectively during carbon starvation and glutamate catabolism in K. phaffii. We conclude that K. phaffii harbours a unique translational regulatory circuit in which substrates of GDH2 and PEPCK act as inducers of their synthesis, a phenomenon not reported in any yeast species.


Assuntos
Glutamato Desidrogenase , Ácidos Cetoglutáricos , Carbono/metabolismo , Regulação Fúngica da Expressão Gênica , Glutamato Desidrogenase/genética , Glutamato Desidrogenase/metabolismo , Glutamatos/metabolismo , Oxaloacetatos , Fosfoenolpiruvato , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Saccharomycetales , Leveduras/metabolismo
6.
Altern Ther Health Med ; 28(6): 65-71, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35452419

RESUMO

Background and Objectives: Colorectal cancer (CRC) is a malignant tumor with an extremely high incidence rate worldwide. This study explores the influence of mindfulness-based stress reduction (MBSR) in the care of patients with CRC undergoing bevacizumab (BVZ) plus XELOX chemotherapy, aiming at providing reliable reference and guidance for further improving their rehabilitation and prognosis. Methods: Between January 2019 and March 2020, 88 patients with CRC admitted consecutively to Jiangsu Cancer Hospital in China were enrolled in the study. Of them, 42 patients receiving BVZ plus XELOX chemotherapy, conventional care and MBSR intervention were assigned to the intervention group, and the remaining 46 patients receiving XELOX chemotherapy and conventional care were included in the control group. Clinical efficacy, safety and improvement in functional status were compared. Patients' psychological state, treatment compliance and self-care ability were evaluated. Finally, prognostic quality of life (QoL) was recorded at 1-year follow-up. Results: The overall response rate and incidence of adverse events in the intervention group were not different in the control group, but the total control rate and improvement rate in the intervention group were higher. After treatment, Sedation-Agitation Scale (SAS) and Self-Rating Depression Scale (SDS) scores in the intervention group were decreased, compliance and self-care ability were improved, all of which were better than in the control group. Prognostic follow-up showed that the QoL in the intervention group was also higher than in the control group. Conclusions: The combined use of BVZ in XELOX-based chemotherapy can improve the clinical outcome and functional status of patients with CRC. In addition, MBSR intervention implemented during chemotherapy can effectively optimize patients' psychological state and treatment compliance, strengthen their self-care ability and improve their prognostic QoL.


Assuntos
Neoplasias Colorretais , Atenção Plena , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/uso terapêutico , Capecitabina , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/tratamento farmacológico , Desoxicitidina/efeitos adversos , Fluoruracila/efeitos adversos , Humanos , Oxaloacetatos , Qualidade de Vida , Resultado do Tratamento
7.
BMC Gastroenterol ; 22(1): 121, 2022 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-35287591

RESUMO

BACKGROUND: Previous studies have confirmed that systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) can predict the prognosis and chemotherapy efficacy of various malignant tumors. However, to the best of our knowledge, no study investigated the SII combined with PNI score to predict the efficacy of anti-programmed death 1 (anti-PD-1) antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in the treatment of locally advanced gastric cancer. This study aims to evaluate the predictive value of pre-treatment SII-PNI score on the sensitivity of sintilimab immunotherapy combined with XELOX chemotherapy in patients with locally advanced gastric cancer. METHODS: We registered a prospective clinical study involving 30 locally advanced gastric cancer patients from March 2020 to July 2021. The pre-treatment SII and PNI were calculated from peripheral blood samples, and the cut-off value was calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 568.5) and low PNI (≤ 52.7); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI. RESULTS: All patients were evaluated by RECIST1.1 criteria after four cycles of sintilimab immunotherapy combined with XELOX chemotherapy, including 5 patients with TRG 3 and 25 patients with non-TRG 3. The SII-PNI score of non-TRG 3 patients was significantly lower than that of TRG 3 patients (P = 0.017). The medial progression free survival of patients with low SII-PNI score was significantly better than that of patients with high SII-PNI score (P < 0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting progression-free survival (P = 0.003). CONCLUSION: The pre-treatment SII-PNI score is a significant indicator for predicting chemosensitivity of locally advanced patients after sintilimab immunotherapy combined with XELOX chemotherapy, which can help to identify high-risk groups and predict prognosis. TRIAL REGISTRATION: The registered name of the trial is "Prospective clinical study of sintilimab combined with chemotherapy for neoadjuvant therapy in locally advanced gastric cancer". Its Current Controlled Trials number is ChiCTR2000030414. Its date of registration is 01/03/2020.


Assuntos
Terapia Neoadjuvante , Neoplasias Gástricas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina/uso terapêutico , Humanos , Imunoterapia , Avaliação Nutricional , Oxaloacetatos , Prognóstico , Receptor de Morte Celular Programada 1 , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico
8.
Gan To Kagaku Ryoho ; 49(2): 226-228, 2022 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-35249069

RESUMO

A 54-year-old woman visited our hospital complaining of abdominal distension. Endoscopic examination revealed type 3 tumor in the rectum located 15 cm from the anal edge. Enhanced computed tomography showed multiple ground glass-like shadows in both lungs that were suspected of multiple metastases. We diagnosed as having rectal cancer with multiple lung metastases. After placing the stent transanally to release the intestinal obstruction, we performed laparoscopic high anterior resection. Then, the patient received chemotherapy with 10 courses of XELOX plus bevacizumab and 9 courses of the regimen without oxaliplatin. A whole-body CT revealed complete response. And while taking capecitabine the patient remains well and without recurrence. We describe the present case with reference to the literature.


Assuntos
Neoplasias Pulmonares , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Capecitabina , Feminino , Fluoruracila , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Pessoa de Meia-Idade , Oxaloacetatos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia
9.
Anticancer Res ; 42(4): 1859-1865, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35347004

RESUMO

BACKGROUND/AIM: This phase II study (MCSGO-1202) aimed to evaluate the initial dose reduction of oxaliplatin in XELOX plus bevacizumab therapy. PATIENTS AND METHODS: This was a phase II, multicenter, open-label, single-arm, prospective, study conducted at 14 Japanese institutions. The study included patients with metastatic colorectal cancer (mCRC) with performance status (PS) of 1 or 2 who had not undergone chemotherapy. Patients received oxaliplatin (100 mg/m2) plus bevacizumab (7.5 mg/kg) on day 1 and capecitabine (2,000 mg/m2/day) on days 1-14 of a 21-day cycle. The primary endpoint was the objective response rate. The secondary endpoints were progression-free and overall survival, 1-year survival rate, disease control rate, dose intensity, and adverse events. RESULTS: Between April 2012 and March 2016, 56 patients were enrolled. The median age was 71 years (range=44-85 years), and the majority (90.6%) had a PS of 1. A complete response was observed in three patients (5.7%), partial response in 24 (45.3%), stable disease in 22 (43.4%), and progressive disease in one (1.9%). The median progression-free survival and overall survival were 11.4 and 26.5 months, respectively. The most common grade 3-4 adverse events were leucopenia (15.1%), neutropenia (9.4%), neuropathy (9.4%). CONCLUSION: The dose-reduction strategy of oxaliplatin was effective for elderly or vulnerable patients with mCRC.


Assuntos
Neoplasias Colorretais , Redução da Medicação , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Capecitabina/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Fluoruracila , Humanos , Compostos Organoplatínicos , Oxaloacetatos , Estudos Prospectivos , Resultado do Tratamento
10.
Cancer Commun (Lond) ; 42(4): 314-326, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35212487

RESUMO

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.


Assuntos
Adenocarcinoma , Neoplasias Hepáticas , Neoplasias Gástricas , Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Oxaliplatina , Oxaloacetatos , Estudos Prospectivos , Qualidade de Vida , Neoplasias Gástricas/patologia
11.
Bioresour Technol ; 345: 126484, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34875371

RESUMO

Effective inducers and stress conditions play an essential role in the regulation of astaxanthin biosynthesis. This study reports a strategy developed by combining exogenous addition of oxaloacetate (OA) with nitrogen deficiency to facilitate astaxanthin production in Haematococcus pluvialis. Significantly, addition of 10 mM-OA enhanced the cellular astaxanthin content about 7.18-fold under nitrogen deficiency on day 7, with the content of astaxanthin esters increased concomitantly. To further elucidate the role and mechanism of OA on astaxanthin synthesis, the physiological and metabolic analyses of H. pluvialis treated with exogenous OA were performed. The results showed that exogenous OA promoted respiration over photosynthesis. Concurrently, the metabolite levels in the Embden-Meyerhof-Parnas pathway, pentose phosphate pathway and tricarboxylic acid cycle obviously increased. The enhancement of respiratory metabolic pathways led to elevated levels of substrates, thus directly promoted astaxanthin synthesis. The present findings provide a new and effective approach for optimizing astaxanthin production.


Assuntos
Clorofíceas , Nitrogênio , Oxaloacetatos , Ácido Oxaloacético , Xantofilas
12.
Eur J Surg Oncol ; 48(1): 188-196, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34479745

RESUMO

OBJECTIVE: The aim of this study was to assess the cost-effectiveness of pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) for the treatment of advanced gastric cancer. METHODS: A Partitioned Survival Model followed by state transition Markov model was developed to estimate the costs and effectiveness of the use of PIPAC C/D versus palliative chemotherapy in the UK. The intervention was assessed at two different levels of care, including upfront therapy (PIPAC C/D plus Oxaliplatin in combination with Capecitabine (XELOX) chemotherapy versus first-line chemotherapy alone) and second-line therapy (PIPAC C/D alone versus second-line chemotherapy (ramucirumab monotherapy)). Data from multiple sources, including published literature and UK-based databases, were used to inform the economic model. RESULTS: For the upfront therapy analysis, the estimated total costs in the intervention and comparator arms were £32,606 (SD: £3877) and £17,844 (SD: £920), respectively. PIPAC C/D plus XELOX led to an increase of 0.46 in quality-adjusted life-years (QALYs) gained. The incremental cost per QALY gained was £31,868. For the second-line therapy analysis, the use of PIPAC C/D led to an increase of 0.19 in QALYs and a £21,474 reduction in costs, meaning the intervention was a dominant strategy. CONCLUSIONS: The cost-effectiveness results for the upfront therapy analysis indicate that PIPAC C/D plus chemotherapy is a cost-effective strategy. Additionally, PIPAC C/D alone as a second-line therapy has the potential to reduce costs and improve clinical outcomes for patients with advanced gastric cancer with peritoneal metastasis.


Assuntos
Aerossóis , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina/uso terapêutico , Carcinoma/tratamento farmacológico , Oxaloacetatos/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Gástricas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/secundário , Cisplatino/administração & dosagem , Análise Custo-Benefício , Doxorrubicina/administração & dosagem , Humanos , Injeções Intraperitoneais , Laparoscopia , Neoplasias Peritoneais/secundário , Anos de Vida Ajustados por Qualidade de Vida , Reino Unido
13.
BMC Cancer ; 21(1): 1111, 2021 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-34656107

RESUMO

BACKGROUND: Among patients with colorectal cancer (CRC) treated with oxaliplatin (L-OHP)-based chemotherapy, delayed chemotherapy-induced nausea and vomiting (CINV) have not been well controlled. METHODS: We pooled data from two prospective observational studies in Japan and one phase III clinical trial to assess whether delayed CINV could be controlled with a combination of three antiemetics adding a neurokinin-1 receptor antagonist and identified individual risk factors, using an inverse probability treatment-weighted analysis. RESULTS: A total of 661 patients were evaluable in this study (median age: 64 years; 391 male, and 270 female). 3 antiemetics controlled delayed nausea (33.18% vs. 42.25%; p = 0.0510) and vomiting (4.15% vs. 16.08%; p < 0.0001) better than with 2 antiemetics. Female and 2 antiemetics were risk factors for both delayed nausea (female-odds ratio [OR]: 1.918; 95% confidence interval [CI]: 1.292-2.848; p = 0.0012; 2 antiemetics-OR: 1.485; 95% CI: 1.000-2.204; p = 0.0498) and delayed vomiting (female-OR: 2.735; 95% CI: 1.410-5.304; p = 0.0029; 2 antiemetics-OR: 4.551; 95% CI: 2.116-9.785; p = 0.0001). CONCLUSIONS: Identifying individual risk factors can facilitate personalized treatments for delayed CINV. We recommend a 3-antiemetic combination prophylaxis for CRC patients treated with L-OHP-based chemotherapy, especially for female patients.


Assuntos
Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Náusea/tratamento farmacológico , Vômito/tratamento farmacológico , Idoso , Capecitabina/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Quimioterapia Combinada , Feminino , Fluoruracila/efeitos adversos , Humanos , Japão , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Estudos Observacionais como Assunto , Compostos Organoplatínicos/efeitos adversos , Oxaloacetatos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores Sexuais , Vômito/induzido quimicamente
14.
Eur J Radiol ; 143: 109887, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34454297

RESUMO

PURPOSE: To assess the value of the enhanced features on the hepatobiliary phase (HBP) of pre-treatment Gd-EOB-DTPA MRI in evaluating response to chemotherapy in colorectal liver metastases (CRLMs). METHODS: We retrospectively studied 65 patients with CRLMs who underwent Gd-EOB-DTPA enhanced MRI before chemotherapy from October 2015 to November 2017. The diagnosis of liver metastasis was established on the basis of imaging findings. Two radiologists evaluated the size, contrast-enhanced (CE) patterns of the maximum lesion on the HBP. According to the different CE patterns, we quantified area signal intensity (SI) by applying SI ratio (such as SIcenter/outer and SIrim/center). All of the above parameters were analyzed in terms of chemotherapy response. RESULTS: Rim enhancement on the HBP was more frequent in the responding group of 28 patients (72%) than in the non-responding group of eight patients (31%). Additionally, there was a significant association between chemotherapy response and quantitative parameters: including diameter (P = 0.04), SIcenter/outer (P = 0.047) and SIrim/center (P = 0.012). The HBP CE pattern (P = 0.007) and SIcenter/outer (P = 0.022) were independent factors for chemotherapy response. The areas under the curve (AUCs) of the above-mentioned parameters were significant associated with response to chemotherapy, in which diameter, HBP CE patterns, SIcenter/outer, and SIrim/center were 0.638, 0.706, 0.712, and 0.673, respectively. Moreover, the combination of these parameters obtained the largest AUC of 0.821. CONCLUSION: The CE patterns, in particular with rim enhancement, and SI ratio parameters on the HBP are useful indicators for early evaluation of therapeutic response after chemotherapy in patients with CRLMs.


Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/tratamento farmacológico , Meios de Contraste , Gadolínio DTPA , Humanos , Fígado , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Imageamento por Ressonância Magnética , Oxaloacetatos , Estudos Retrospectivos
15.
Anticancer Drugs ; 32(10): 1123-1126, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34261916

RESUMO

Cetuximab is an IgG1 chimeric mAb against epidermal growth factor receptor, which can be used for chemotherapy failure or tolerance in patients with epidermal growth factor receptor expressed RAS wild-type metastatic colorectal cancer. We report on a patient who developed rapid-onset interstitial pneumonia while being treated with cetuximab plus XELOX (oxaliplatin, capecitabine) for metastatic colorectal cancer. A 75-year-old man patient was administered cetuximab plus XELOX regularly. After his cetuximab schedule was adjusted from 1 to 2 weeks, he rapidly developed interstitial pneumonia which led to acute respiratory distress syndrome. Our literature review indicated that, for patients with risk factors, a 2-week regimen of cetuximab might lead to interstitial pneumonia. Clinicians should closely monitor patients for adverse drug reactions to improve drug safety.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Cetuximab/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Capecitabina , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Humanos , Masculino , Metástase Neoplásica , Oxaloacetatos
16.
Br J Radiol ; 94(1124): 20201088, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34260297

RESUMO

OBJECTIVE: The aim of this study was to compare the clinical efficacy of neoadjuvant chemoradiotherapy (NACRT) combined with postoperative adjuvant XELOX (Oxaliplatin +Capecitabine) chemotherapy and postoperative adjuvant chemotherapy (ACT) with XELOX for local advanced gastric cancer (LAGC). METHODS: In this prospectively randomized trial, we investigated the effect of NACRT combined with postoperative ACT for LAGC. 60 patients were randomly divided into NACRT group and ACT group, with 30 patients in each group. Patients in NACRT group were given three-dimensional conformal radiotherapy (45 Gy/1.8 Gy/f) accompanied by synchronous XELOX of two cycles, followed by surgery, and then postoperative adjuvant XELOX chemotherapy of four cycles was performed. Patients in ACT group received surgery in advance, and then XELOX chemotherapy of six cycles was given. RESULTS: The objective response rate of NACRT was 76.7%. The overall incidence of postoperative complications in NACRT group was not significantly different from that in ACT group (23.1% vs 30.0%, p = 0.560). The 1 year, 2 years, and 3 years progression-free survival (PFS)and overall survival (OS) in NACRT and ACT groups were 80.0% vs 56.7%, 73.3% vs 46.7%, 60.0% vs 33.3%, and 86.7% vs 80.0%, 76.7% vs 66.7%, 63.3% vs 50.0%, respectively. Patients in NACRT group showed a significantly higher R0 resection rate (84.6% vs 56.7%, p = 0.029),lower loco-regional recurrence rate (36.7% vs 11.5%, p = 0.039), longer PFS (p = 0.019) and freedom from locoregional progression(FFLP) (p = 0.004) than patients in ACT group, while there was no difference in OS (p = 0.215) and in toxicity incidence (p > 0.05). CONCLUSIONS: NACRT combined with postoperative adjuvant XELOX chemotherapy can improve R0 resection rate, reduce loco-regional recurrence, prolong PFS and FFLP without increasing the incidence of postoperative complications in patients with LAGC. ADVANCES IN KNOWLEDGE: Compared with postoperative adjuvant chemotherapy, locally advanced gastric cancer patients may benefit from neoadjuvant chemoradiotherapy, and toxicity associated with chemoradiotherapy was tolerant and manageable.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Oxaloacetatos/uso terapêutico , Radioterapia Conformacional , Neoplasias Gástricas/terapia , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Período Pós-Operatório , Estudos Prospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do Tratamento
17.
JNCI Cancer Spectr ; 5(1)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-34159294

RESUMO

Background: SCOT was an international, randomized phase 3 trial of 3 months vs 6 months of adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine in patients with colorectal cancer. We sought patients' preferences for 3 months vs 6 months of adjuvant chemotherapy in the SCOT trial. Methods: SCOT participants from Australia and New Zealand completed a validated questionnaire (at 3 and 18 months) to elicit the minimum survival benefits judged necessary to make an extra 3 months of adjuvant chemotherapy worthwhile, based on their experience. Standardized hypothetical scenarios used the following baseline survivals (with 3 months of chemotherapy): life expectancies (LE) of 5 years and 15 years and 5-year survival rates (5YS) of 65% and 85%. Results: Of the 160 participants, 82 were assigned 3 months adjuvant chemotherapy, and 78 were assigned 6 months. Adjuvant chemotherapy was FOLFOX in 121 (75.6%) and XELOX in 39 (24.4%). Preferences varied substantially and did not differ according to treatment group. The median survival benefits judged necessary to make the extra 3 months of chemotherapy worthwhile were an extra 3 years beyond a LE of 5 years; 3 years beyond a LE of 15 years; 15% beyond a 5YS of 65%; and 5% beyond a 5YS of 85%. Preferences were similar at 3 months and 18 months. Preferences were not predicted by participants' baseline characteristics. Conclusion: Preferences varied substantially, and the benefits many required to warrant an extra 3 months of adjuvant chemotherapy were larger than the benefits of an extra 3 months of chemotherapy calculated in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) meta-analysis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Preferência do Paciente , Austrália , Capecitabina/administração & dosagem , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/estatística & dados numéricos , Neoplasias do Colo/mortalidade , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina/administração & dosagem , Oxaloacetatos/administração & dosagem , Estudos Prospectivos , Inquéritos e Questionários , Taxa de Sobrevida
18.
BioDrugs ; 35(4): 445-458, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34014555

RESUMO

BACKGROUND: HLX04 is a proposed biosimilar of bevacizumab. OBJECTIVE: This phase III study aimed to evaluate the efficacy, safety, and immunogenicity of HLX04 compared with reference bevacizumab in combination with XELOX or mFOLFOX6 as first-line treatment for recurrent/metastatic colorectal cancer (CRC). METHODS: In this double-blind, parallel-group study, patients were randomized 1:1 to receive HLX04 or bevacizumab (7.5 mg/kg every 3 weeks when combined with XELOX; 5 mg/kg every 2 weeks when combined with mFOLFOX6). The primary endpoint was progression-free survival rate at week 36 (PFSR36w) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Prespecified equivalence margins of PFSR36w were set as - 11 to 15% (rate difference) and 0.8 to 1.25 (rate ratio). Secondary endpoints included efficacy, safety, immunogenicity, and pharmacokinetics. RESULTS: A total of 677 patients were randomized (HLX04 n = 340; bevacizumab n = 337) between April 2018 and April 2020. PFSR36w was 46.4% (95% confidence interval [CI] 41.1-51.8) with HLX04 and 50.7% (95% CI 45.4-56.1) with bevacizumab. The rate difference (- 4.2%; 90% CI - 10.6 to 2.1) and rate ratio (0.92; 90% CI 0.80-1.05) both fell within the prespecified equivalence margins. No notable differences were observed between treatment groups in any efficacy endpoints or their subgroup analyses. Safety, immunogenicity, and pharmacokinetic profiles were comparable between the two treatment groups. CONCLUSIONS: HLX04 demonstrated equivalent efficacy with similar safety and immunogenicity profiles to reference bevacizumab among patients with recurrent/metastatic CRC, thus offering an alternative treatment option to patients. TRIAL REGISTRATION: Chinadrugtrials.org.cn, CTR20171503 (18 March 2018); ClinicalTrials.gov, NCT03511963 (30 April 2018).


Colorectal cancer (CRC) is the third most common cancer worldwide. Approximately 20% of patients with CRC have metastases at their first visit. Bevacizumab is a biologic antibody approved in many countries for the treatment of metastatic CRC. However, high treatment costs significantly limit patient access to bevacizumab. Therefore, HLX04, a potential bevacizumab biosimilar, which is almost identical to bevacizumab but less expensive and more accessible, has been developed. This randomized clinical trial was designed to evaluate the efficacy (ability of a drug to produce the desired treatment effects), safety, and immunogenicity (ability of a drug to induce immune response that would affect its efficacy and safety) of HLX04 compared with the reference bevacizumab in patients with recurrent/metastatic CRC. Efficacy of the tested drug was evaluated by comparing the proportion of patients without disease progression or death at week 36 (PFSR36w). Safety was monitored using adverse events and other clinical evaluations. Immunogenicity was assessed by the incidence of antidrug antibodies. Of the 677 patients enrolled in the study, 340 received HLX04 and 337 received bevacizumab. Statistical analyses showed that HLX04 was equivalent to bevacizumab in efficacy evaluations (the difference in PFSR36w between the two treatment groups fell within the prespecified "equivalence margins"). Moreover, the two treatments were similar with respect to safety and immunogenicity evaluations. In summary, patients responded equally well to HLX04 and bevacizumab, supporting the development of HLX04 as a proposed biosimilar to bevacizumab for patients with recurrent/metastatic CRC.


Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Capecitabina , Neoplasias Colorretais/tratamento farmacológico , Método Duplo-Cego , Humanos , Oxaloacetatos
20.
Medicine (Baltimore) ; 100(17): e25493, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907099

RESUMO

BACKGROUND: A combination of fluoropyrimidines and platinum is widely accepted as the standard first-line treatment for advanced gastric and gastroesophageal adenocarcinomas. However, the benefit compared with platinum-free chemotherapeutic regimens remains controversial. We compared the efficacy and safety of capecitabine with oxaliplatin or docetaxel, as first-line therapy in advanced gastric cancer. METHODS: Eligible patients were randomly assigned to receive either capecitabine and oxaliplatin (XELOX) (capecitabine 1,000 mg/m2; twice daily for 14 days with oxaliplatin 130 mg/m2 on day 1, every 21 days), or DX (capecitabine 1,000 mg/m2; twice daily for 14 days with docetaxel 75 mg/m2 on day 1, every 21 days). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival, overall survival, and prespecified safety endpoints. RESULTS: Ninety patients were enrolled in the West China Hospital from April 2012 to August 2016; a total of 83 and 66 patients were eligible for safety and efficacy analyses, respectively. Between the XELOX and DX groups, ORR (24.2% vs 24.2%, p = 1.000), DCR (90.9% vs 75.8%, p = 0.099), progression-free survival (6.1m vs 4.1m, p = 0.346), and overall survival (8.8m vs 9.0m, p = 0.973) were similar. There was no significant difference in toxicity between the two regimens. The frequent grade 3 or higher toxicities in the XELOX and DX groups were peripheral neuropathy and hematological toxicity, respectively. Toxicity was tolerable; no treatment-related deaths occurred in either group. CONCLUSIONS: The DX regimen was not superior to XELOX, but instead, similar. The platinum-containing regimen remains the preferred first-line option for advanced gastric and gastroesophageal adenocarcinomas, and DX might be considered as an alternative for patients unsuitable for platinum-containing chemotherapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaloacetatos/uso terapêutico , Intervalo Livre de Progressão , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida
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