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Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.
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Flavonoides , Glicólise , Neoplasias Ovarianas , Propiofenonas , Proteínas Quinases Associadas a Fase S , Ubiquitinação , Propiofenonas/farmacologia , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Flavonoides/farmacologia , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Glicólise/efeitos dos fármacos , Animais , Transdução de Sinais/efeitos dos fármacos , Caderinas/metabolismo , Carcinogênese/efeitos dos fármacos , Antígenos CD/metabolismo , Hexoquinase/metabolismo , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Fitoterapia , Camundongos Nus , Antineoplásicos Fitogênicos/farmacologiaRESUMO
INTRODUCTION: Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. METHODS: Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). RESULTS: Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. CONCLUSIONS: The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.
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Benzofuranos , Neoplasias Colorretais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Benzofuranos/efeitos adversos , Benzofuranos/uso terapêutico , Benzofuranos/administração & dosagem , Adulto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Quinazolinas/efeitos adversos , Quinazolinas/uso terapêutico , Quinazolinas/administração & dosagem , China , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , População do Leste AsiáticoRESUMO
Background: To construct an effective prognostic index to predict overall survival (OS) and triplet regimen efficacy for advanced gastric cancer (AGC) patients treated with platinum-based and fluorouracil-based chemotherapy. Objectives: Between 2011 and 2021, 679 patients from two randomized phase III trials and one phase II trial were enrolled. Designs: We collected 11 baseline clinicopathological and 14 hematological parameters to establish a prognostic index. Methods: Univariate and multivariate Cox analyses were used to screen prognostic factors, and a prognostic index nomogram was conducted. Results: Seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic nomogram named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in the low-risk group (median OS, 15.5 versus 8.0 months, p < 0.001). The areas under the curve of the FARS index for 1-, 2-, and 3-year OS were 0.70, 0.72, and 0.77, respectively. A validation and external cohort verified the prognostic value of the FARS index. Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (p = 0.018). Conclusion: The constructed FARS index to predict the OS of AGC patients and the TRIS index to screen out the dominant population for triplet regimens can be used to aid clinical decision-making and individual risk stratification.
A prognostic index in locally advanced and metastatic gastric cancer To date, no recognized systematic prognostic score has been established for advanced gastric cancer (AGC). Our research aims to construct an effective prognostic index to predict overall survival (OS) for AGC patients to aid clinical decision-making and individual risk stratification. In our research, seven prognostic factors were identified: primary tumor site in the non-proximal gastric area, signet-ring cell carcinoma (SRCC)/mucinous carcinoma, peritoneal metastasis, neutrophil count higher than the upper limit of normal value (ULN), lymphocyte count lower than the lower limit of normal value, lactate dehydrogenase level higher than the ULN, and alkaline phosphatase level higher than the ULN as significant for prognosis. A prognostic index named the Fudan advanced gastric cancer prognostic risk score (FARS) index was constructed, and patients in the high-risk group had significantly shorter OS than those in low-risk group (median OS, 15.5 months vs. 8.0 months, P < 0.001). Moreover, three triplet regimen efficacy parameters were identified: SRCC/mucinous adenocarcinoma, primary tumor location in the non-proximal gastric area, and peripheral neutrophil count higher than the ULN; a TRIS index was subsequently conducted. In patients with any two of the three parameters, the triplet regimen showed significantly longer OS than the doublet regimen (P = 0.018).
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Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy. Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021. Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years. Main Outcomes and Measures: The primary end point was overall survival time from randomization. Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%). Conclusions and Relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03745170.
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Adenocarcinoma , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Junção Esofagogástrica , Neoplasias Gástricas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoglobulina G/imunologia , Método Duplo-Cego , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Oxaloacetatos/administração & dosagem , Oxaloacetatos/efeitos adversosRESUMO
We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200 mg every 3 weeks. The most common cancer type is colorectal cancer (n = 71). With a median follow-up of 22.5 months, the objective response rate is 49.0% (95% confidence interval 38.86%-59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2D gene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2D mutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.
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Neoplasias Colorretais , Instabilidade de Microssatélites , Humanos , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resultado do TratamentoRESUMO
PURPOSE: Lymphocyte-monocyte ratio (LMR) has previously been used as a prognostic predictor in various solid tumors. This research aims in comparing the prognostic predictive Please check and conability of several inflammatory parameters and clinical parameters to validate further the excellent prognostic value of LMR in patients with gastric cancer treated with apatinib. METHODS: Monitor inflammatory, nutritional parameters and tumor markers. Cutoff values of the parameters concerned were identified with the X-tile program. Subgroup analysis was made via Kaplan-Meier curves, and univariate and multivariate Cox regression analyses were used to find independent prognostic factors. The nomogram of logistic regression models was constructed according to the results. RESULTS: A total of 192 patients (115 divided into training group and 77 into validation group) who received the second- or later-line regimen of apatinib were retrospectively analyzed. The optimal cutoff value for LMR was 1.33. Patients with high LMR (LMR-H) were significantly longer than those with low LMR (LMR-L) in progression-free survival (median 121.0 days vs. median 44.5 days, P < 0.001). The predictive value of LMR was generally uniform across subgroups. Meanwhile, LMR and CA19-9 were the only hematological parameters with significant prognostic value in multivariate analysis. The area under the LMR curve (0.60) was greatest for all inflammatory indices. Adding LMR to the base model significantly enhanced the predictive power of the 6-month probability of disease progression (PD). The LMR-based nomogram showed good predictive power and discrimination in external validation. CONCLUSION: LMR is a simple but effective predictor of prognosis for patients treated with apatinib.
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Monócitos , Neoplasias Gástricas , Humanos , Monócitos/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Estudos Retrospectivos , Linfócitos/patologiaRESUMO
BACKGROUND: Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. METHODS: Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. RESULTS: Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). CONCLUSIONS: The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.
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Adenocarcinoma , Antineoplásicos , Neoplasias Gástricas , Humanos , Antineoplásicos/efeitos adversos , Neoplasias Gástricas/tratamento farmacológico , Estudos Prospectivos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Junção Esofagogástrica/patologiaRESUMO
Background: Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient's prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis. Objective: NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury. Methods: In this study, we used wild-type mice and hsf1 -/- mice for in vivo research and PC12 cells for in vitro research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells. Results: The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the hsf1 -/- mouse model compared to hsf1 +/+ mice. In PC12 cells, hsf1 siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while hsf1 siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by nlrp3 siRNA. Conclusion: These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.
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Lesões Encefálicas , Fatores de Transcrição de Choque Térmico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sepse , Animais , Camundongos , Ratos , Fatores de Transcrição de Choque Térmico/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , RNA Interferente Pequeno , Sepse/metabolismoRESUMO
Objective: To explore the effect and safety of avatrombopag for chemotherapy-induced thrombocytopenia (CIT). Methods: This multicenter, open-label, single-arm trial enrolled CIT patients in eight centers from October 2020 to April 2021. The participants received avatrombopag tablets 60 mg once a day for 5-10 days. The main endpoint was the proportion of patients with platelet count ≥100×109/L or increased by ≥ 50×109/L or increased by ≥ 100% in the cycle after the start of treatment. Results: Seventy-four participants were enrolled with a mean age of 59.8 ± 11.62.2% were males. The cumulative effective rate (any criteria) was 70.3% at 4 weeks. 42 (56.8%) achieved platelet count ≥100×109/L, 44 (59.5%) increased by ≥ 50×109/L, and 27 (36.5%) increase by ≥ 100% from baseline. The duration of grade III and IV platelet reduction was 4.2 ± 5.3 days. The time of PLT recovery to ≥75×109/L was 9.4 ± 6.6 days. The time of PLT recovery to ≥100×109/L was 10.2 ± 6.4 days. The platelet count nadir was 57.9 ± 45.3×109/L. The most common adverse events were nausea (8.1%), fatigue (5.4%), and abdominal pain (1.4%). There were no cases of fever, headache, or peripheral edema. Conclusion: Although it was a single-arm trial without a control group, the application of avatrombopag in patients with CIT can increase the platelet count of the patients compared with baseline. Avatrombopag is safe and tolerable. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04609891?term=04609891&draw=2&rank=1, identifier [NCT04609891].
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Introduction: No effective peripheral blood predictors have been establoshed for first-line chemotherapy in patients with advanced gastric cancer. In this study, a nomogram combining the neutrophil-to-lymphocyte ratio/D-dimer with gender, number of metastases, and histological grade was established to predict progression-free survival in patients with unresectable advanced gastric cancer. Methods: We retrospectively collected baseline clinical characteristics and blood parameters from 153 patients diagnosed with advanced gastric cancer that underwent oxaliplatin-based first-line chemotherapy. Kaplan-Meier analysis and Cox regression analysis were used to determine the factors associated with progression-free survival. The concordance index (C-index) and calibration curve were used to determine the prediction accuracy and discriminative ability of the nomogram as a visual complement to the prognostic score system. Results: Determined by the X-tile software, the optimal cut-off points for the neutrophil-to-lymphocyte ratio and D-dimer were 3.18 and 0.56â mg/L, respectively. Multivariate analysis identified four independent prognostic factors: two or more metastatic organs (HR: 1.562, 95% CI: 1.009-2.418, P = .046), poor differentiation (HR: 0.308, 95% CI: 0.194-0.487, P < .001), neutrophil-to-lymphocyte ratio >3.18 (HR: 1.427, 95% CI: 1.024-1.989, P = .036), and D-dimer >0.56â mg/L (HR: 1.811, 95% CI: 1.183-2.773, P = .006). Receiver operating characteristic curves showed that the combination of the neutrophil-to-lymphocyte ratio and D-dimer in the prediction model exhibited the highest predictive performance (area under the curve, 0.800). The prognostic nomogram yielded a C-index of 0.800. Decision curve analysis demonstrated that the prognostic nomogram was clinically useful. A nomogram-based risk classification system was also constructed to facilitate risk stratification of advanced gastric cancer for optimal clinical management. Conclusion: We identified the neutrophil-to-lymphocyte ratio and D-dimer level as independent prognostic factors for advanced gastric cancer. The prognostic nomogram combining the neutrophil-to-lymphocyte ratio and D-dimer level can be applied in the individualized prediction of treatment outcome in patients with advanced gastric cancer.
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Neutrófilos , Neoplasias Gástricas , Produtos de Degradação da Fibrina e do Fibrinogênio , Humanos , Linfócitos/patologia , Neutrófilos/patologia , Nomogramas , Oxaliplatina , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologiaRESUMO
Objectives: This study aimed to create a nomogram for the risk prediction of neoadjuvant chemoradiotherapy (nCRT) resistance in locally advanced rectal cancer (LARC). Methods: Clinical data in this retrospective study were collected from a total of 135 LARC patients admitted to our hospital from June 2016 to December 2020. After screening by inclusion and exclusion criteria, 62 patients were included in the study. Texture analysis (TA) was performed on T2WI and DWI images. Patients were divided into response group (CR+PR) and no-response group (SD+PD) according to efficacy assessment. Multivariate analysis was performed on clinicopathology, IVIM-DWI and texture parameters for screening of independent predictors. A nomogram was created and model fit and clinical net benefit were assessed. Results: Multivariate analysis of clinicopathology parameters showed that the differentiation and T stage were independent predictors (OR values were 14.516 and 11.589, resp.; P<0.05). Multivariate analysis of IVIM-DWI and texture parameters showed that f value and Rads-score were independent predictors (OR values were 0.855, 2.790, resp.; P<0.05). In this study, clinicopathology together with IVIM-DWI and texture parameters showed the best predictive efficacy (AUC=0.979). The nomogram showed good predictive performance and stability in identifying high-risk LARC patients who are resistant to nCRT (C-index=0.979). Decision curve analyses showed that the nomogram had the best clinical net benefit. Ten-fold cross-validation results showed that the average AUC value was 0.967, and the average C-index was 0.966. Conclusions: The nomogram combining the differentiation, T stage, f value and Rads-score can effectively estimate the risk of nCRT resistance in patients with LARC.
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Hepatitis B virus (HBV) infection has been reported to be associated with gastric cancer (GC). Nonetheless, no study has revealed the role of HBV infection in the survival of patients with GC, and the mutation profiles of HBV-infected patients with GC have never been documented. Here, we performed an updated meta-analysis and found a significantly increased risk of GC in HBV-infected individuals (sOR, 1.29; 95% CI, 1.22-1.37). Furthermore, we observed that in the Anhui area, the rate of serum HBsAg positivity (OR, 1.62; 95% CI, 1.03-2.55) was significantly higher in GC patients than in controls. Moreover, our results showed that HBV-positive patients had significantly worse disease-free survival (HR, 1.98; 95% CI, 1.39-2.82) and overall survival (HR, 1.84; 95% CI, 1.19-2.85) than HBV-negative patients. The results of Cox proportional hazards regression proved that HBV infection was an independent adverse prognostic factor in GC. Furthermore, by performing targeted-NGS, we found unique mutation profiles in HBV-infected GC samples, including five frequently mutated protein-coding genes (KMT2B, KMT2D, SOX1, FGF12, and TUBB2B). Expression and survival analyses of these genes identified three novel candidate genes that may have potential roles in GC development. Gene Ontology enrichment analysis showed that the recurrent mutations in HBV-positive GC samples were related to cell proliferation, cell migration, and transcription. Taking together, our study proved that HBV infection is an independent prognostic factor in GC patients. The unique mutation profiles of HBV-infected patients with GC open a new research direction toward the underling mechanism between HBV infection and GC.
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Hepatite B , Neoplasias Gástricas , DNA Viral , Fatores de Crescimento de Fibroblastos , Hepatite B/complicações , Hepatite B/genética , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Humanos , Mutação , Neoplasias Gástricas/complicações , Neoplasias Gástricas/genéticaRESUMO
Background: Previous studies of the second-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJAC) had reported that apatinib combined with chemotherapy improved the treatment outcomes. However, the benefits were sometimes limited due to the tolerance of continuous dose regimen. This randomized controlled study aimed to investigate the efficacy and safety of intermittent or continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Methods: Advanced GC/GEJAC patients who failed first-line chemotherapy were recruited (enrollment time: from September 15, 2017 to July 21, 2019), and randomly assigned to either the intermittent dose group (IG group) or the continuous dose group (CG group) (1:1 ratio) using the block randomization method. In the IG group, patients received apatinib 500 mg/d for 5 consecutive days then held for 2 days plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. In the CG group, patients received apatinib 500 mg daily plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. The progression free survival (PFS) was evaluated every two cycles and follow-ups were performed monthly. The primary endpoint was PFS, and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: In total, 76 eligible patients were enrolled and randomly assigned (1:1 ratio). The IG group exhibited similar PFS compared to the CG group [median PFS: 3.88 (95% CI: 1.72-6.03) months vs. 3.98 (95% CI: 1.06-6.90) months, P=0.546] and OS [median OS: 9.00 (95% CI: 5.31-12.70) months vs. 9.40 (95% CI: 5.20-13.59) months, P=0.310]. ORR (21.1% vs. 18.4%, P=0.773) and DCR (60.5% vs. 60.5%, P=1.000) were of not statistically different between the IG and CG groups. As for safety, the IG group exhibited less frequent hypoproteinemia (31.6% vs. 55.3%, P=0.037) and lactate dehydrogenase increased (18.4% vs. 44.7%, P=0.014), while no differences in other adverse events were observed between the two groups. Conclusions: Intermittent dose apatinib plus docetaxel was equally effective and more tolerable than continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC. Trial Registration: ClinicalTrials.gov NCT03334591.
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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.
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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/patologiaRESUMO
BACKGROUND: To explore the clinicopathological significance and prognostic value of thiopurine methyltransferase (TPMT) in patients with colon cancer by bioinformatics analysis. MATERIALS AND METHODS: The clinicopathological information and TPMT expression data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Wilcoxon signed-rank test was used to evaluate the relationship between TPMT mRNA expression levels and clinicopathological characteristics in patients with colon cancer. Then, the prognostic value of TPMT mRNA expression for disease-free survival (DFS) and overall survival (OS) in patients with colon cancer was assessed by Kaplan-Meier and Cox regression analyses. Additionally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore potential functions of TPMT in patients with colon cancer. RESULTS: TPMT mRNA was significantly downregulated in colon cancer compared with normal tissues (P < 0.05). Wilcoxon analysis revealed that lower TPMT mRNA expression was remarkably associated with lymph node metastasis (P = 0.008), distant metastasis (P = 0.012) and advanced pathological stage (P = 0.010). Besides, the high TPMT mRNA level was also correlated with a favorable DFS and OS in colon cancer patients (both P < 0.05). Moreover, GO enrichment analysis indicated that the co-expressed genes of TPMT function as extracellular matrix (ECM) structural constituent, insulin-like growth factor binding, cell adhesion molecule binding and growth factor binding. KEGG enrichment analysis suggested that the co-expressed genes of TPMT were particularly enriched in amino sugar and nucleotide sugar metabolism, ECM-receptor interaction and focal adhesion. CONCLUSION: TPMT mRNA level might be a novel prognostic biomarker for patients with colon cancer.
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Background: Apatinib has a certain efficacy for advanced esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the prognostic significance of platelet (PLT) and platelet to mean platelet volume (PLT/MPV) ratio for advanced ESCC patients with apatinib second-line or late-line treatment. Methods: A retrospective study included 80 patients with advanced ESCC who received Apatinib ≥ 2 lines targeted therapy. We collected baseline clinical characteristics and blood parameters from the patients. Kaplan-Meier plots and univariate and multivariate analysis were used to find the factors related to progression-free survival (PFS). Results: The optimal cut-off values of PLT and PLT/MPV ratio were determined by X-tile software. Kaplan-Meier analysis demonstrated that patients in the high PLT group had better PFS than those in the low PLT group (156 d vs 80 d, P <.001), and patients in the high PLT/MPV ratio group had better PFS than those in low PLT/MPV ratio group (157 d vs 85 d, P <.001). Univariate analysis revealed pretreatment PLT and PLT/MPV ratio were significantly correlated with PFS. Multivariate analysis revealed high levels of pretreatment PLT/MPV ratio was an independent predictor of longer PFS (HR: 0.257, 95% CI: 0.089-0.743, P = .012). Conclusion: High levels of baseline PLT and PLT/MPV may indicate a better prognosis in apatinib ≥ 2 lines treatment for advanced ESCC patients.
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Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/mortalidade , Volume Plaquetário Médio , Contagem de Plaquetas , Adulto , Idoso , Terapia Combinada , Carcinoma de Células Escamosas do Esôfago/diagnóstico , Carcinoma de Células Escamosas do Esôfago/terapia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Retratamento , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: FOLFIRI [irinotecan, folinic acid (CF), and fluorouracil] is considered a standard second-line chemotherapy regimen for patients with metastatic colorectal cancer (mCRC) who failed first-line XELOX/FOLFOX regimens. However, it remains unknown whether fluorouracil is still necessary in this case. This trial was designed to test the superiority of FOLFIRI over single-agent irinotecan as a second-line treatment for patients with mCRC. METHODS: This randomized clinical trial was conducted in five hospitals in China. From 4 November 2016 to 17 January 2020, patients aged 18 years or older with histologically confirmed unresectable mCRC and who had failed first-line XELOX/FOLFOX regimens were screened and enrolled. Patients were randomized to receive either FOLFIRI or irinotecan. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and toxicity. Data were analyzed on an intention-to-treat basis. RESULTS: A total of 172 patients with mCRC were randomly treated with FOLFIRI (n = 88) or irinotecan (n = 84). The median PFS was 104 and 112 days (3.5 and 3.7 months) in the FOLFIRI and irinotecan groups, respectively [hazard ratio (HR) = 1.084, 95% confidence interval (CI) = 0.7911-1.485; p = 0.6094], and there was also no significant difference in OS and ORR between the two groups. The incidence of the following adverse events (AEs) was significantly higher in the FOLFIRI group than in the irinotecan group: any grade AEs including leucopenia (73.9% versus 55.4%), neutropenia (72.7% versus 56.6%), thrombocytopenia (31.8% versus 18.1%), jaundice (18.2% versus 7.2%), mucositis (40.9% versus 14.5%), vomiting (37.5% versus 21.7%), and fever (19.3% versus 7.2%) and grade 3-4 neutropenia (47.7% versus 21.7%). CONCLUSION: This is the first head-to-head trial showing that single-agent irinotecan yielded PFS, OS, and ORR similar to FOLFIRI, with a more favorable toxicity profile; therefore, it might be a more favorable standard chemotherapy regimen for mCRC patients who failed first-line XELOX/FOLFOX regimens. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT02935764, registered 17 October 2016, https://clinicaltrials.gov/ct2/show/NCT02935764.
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Background: Recent studies have found that 5-methylcytosine (m5C) modulators are associated with the prognosis and treatment of cancer. However, the relevance of m5C modulators in sarcoma prognosis and the tumour microenvironment is unclear. Methods: We selected 15 m5C regulators and performed unsupervised clustering to identify m5C modification patterns and differentially expressed genes associated with the m5C phenotype in The Cancer Genome Atlas (TCGA) sarcomas. The extent of immune cell infiltration in different clustering groups was explored using single-sample gene set enrichment analysis and estimation algorithms. A principal component analysis algorithm-based m5C scoring protocol was performed to assess the m5C modification patterns of individual tumors. Results: We identified two distinct m5C modification patterns in the TCGA sarcoma cohort, which possess different clinical outcomes and biological processes. Tumour microenvironment analysis revealed two groups of immune infiltration patterns highly consistent with m5C modification patterns, classified as immune inflammatory and immune desert types. We constructed m5C scores and found that high m5C scores were closely associated with leiomyosarcoma and other subtypes, and were associated with poorer prognosis, lower PD-L1 expression, and poorer immunotherapy outcomes. The best application was validated against the m5C database. Conclusion: We constructed an m5C score for sarcoma based on the TCGA database and identified a poorer prognosis in the high m5c score group. The stability and good prognostic predictive power of the m5C score was verified by an external database. We found that sarcomas in the low m5C score group may have a better response to immunotherapy.
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BACKGROUND: Postoperative analgesia is widely used for patients undergoing major surgeries. Individual differences in genetic polymorphisms may be obstructive factors for accurately anesthetics using. However, the equation for predicting sufentanil dosage postoperatively based on genetic design has been established yet. Our aim was to establish sufentanil dosage postoperatively prediction equation based on patients' genetic polymorphisms. METHODS: One hundred forty patients with total gastrectomy and radical resection of pulmonary carcinoma were included. To establish sufentanil dosage postoperatively for patients with gastric cancer, we collected patients' basic information and CYP3A4*1G, COMTVal158Met, OPRM1A118G, and ABCB1C3435T gene sequencing results. To verify this equation, we put patients' with lung cancer surgeries information into it. RESULTS: The sufentanil dosage prediction equation postoperatively was y = 4.104 - 0.222 × (gender) + 0.021 × (OPRM1A118G) + 0.249 × (ABCB1C3435T). Patients' with lung cancer surgeries information were substituted into it. The results showed no significant differences between predicted and actual sufentanil dosage (p > 0.05). CONCLUSION: We established the prediction equation for individual sufentanil dosage postoperatively based on gene polymorphisms. The results showed this prediction equation was valid, which might be used for different types of surgeries. We established an equation for individual dosage of sufentanil for postoperative analgesia based on gene polymorphisms. The results show that the prediction equation is valid, the information might be used for different types of postoperative analgesia, and the painful patients will have great potential safe and personalized pain control after analgesic therapy. It might also have potential as a clinical tool.