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Objective To explore the effect of sorafenib on HeLa cell proliferation by inducing cell apoptosis and autophagy and its impact on drug resistance.Methods The drug-resistant cell strains were constructed through in-termittent induction method,with concentrations of 0,2.5,5.0,7.5,10.0,15.0,20.0 μmol/L.HeLa cells were incubated with increasing concentrations of sorafenib with each concentration for 1 week.The drug-resistant cell strains with stable passages were collected.MTT assay was used to detect the effect of sorafenib on cell prolifer-ation.Cell cycle distribution was analyzed by flow cytometry.The change in the expression of drug-resistant and ap-optotic genes in the parents and drug-resistant cell strains under different drug concentrations was examined by semi-quantitative PCR.The changes of apoptotic related marker proteins LC3-Ⅰ and LC3-Ⅱ were detected by Westernblot.Results Stable drug-resistant strains were successfully obtained;Drug-treated cells were more blocked in the G1 phase.In drug-resistant cells,the expression of apoptosis suppressor gene Bcl-2 was significantly decreased and the apoptotic gene Bax as well as the drug-resistant genes were all significantly increased(P＜0.05).The LC3-Ⅱ/LC3-Ⅰ ratio of drug-resistant cells was significantly higher than that of parent cells(P＜0.05).Conclusions Sorafenib may block the cell cycle,suppress malignant cell proliferation and promote autophage.On one hand,autophagy participates in the development of cell drug resistance and promotes cell survival.On the other hand,drug-induced autophagy may activate some of apoptotic signaling pathway in drug-resistant cells and promote the reversal of cell drug resistance.
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A 67-year-old female patient with postoperative recurrence of stage Ⅳright renal cell carcinoma and multiple intracranial metastases was treated with sorafenib and sintilimab.Within 2 weeks,the patient had a fever and red spotted rash in facial,back,buttocks and limb.After 2 days,the fever completely relieved,but subcutaneous exudation appeared on the skin of both elbow joints,buttocks,and outer thighs,followed by gradual epidermal lysis and detachment with skin ulceration.After 4 days,the patient's epidermolysis area was greater than 30％of the body surface area.The patient was diagnosed with toxic epidermal necrolysis(TEN).The adverse reaction correlation was assessed by ALDEN SCORE sheet.The adverse reaction of TEN was"likely"caused by sorafenib and sintilimab.After withdrawal and treatment,the TEN was cured.This paper explores the correlation between the TEN and the combination use of sorafenib and sintilimab and the management.This paper will provide reference for the early diagnosis and correct treatment of TEN.
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Objective To compare the cost-utility of tislelizumab and sorafenib in the first-line treatment of advanced unresectable hepatocellular carcinoma,and to provide a reference for the selection of treatment regimens from the perspective of pharmacoeconomics.Methods A partitioned survival model was used to simulate the survival status of patients using tislelizumab or sorafenib within 10 years,and the cost and health output were calculated respectively to obtain the incremental cost-utility ratio(ICUR).The 3 times China's per capita gross domestic product(GDP)in 2022 was taken as the threshold for willingness to pay(WTP).Results During the simulation period,the ICER of tislelizumab versus sorafenib was 280 691.4 yuan/quality-adjusted life year(QALY),which was significantly higher than that of the sorafenib group,which had obvious economic performance.Univariate sensitivity analysis showed that the incidence of grade 3 or above adverse reactions in the tislelizumab group,the cost of tislelizumab,and the incidence of grade 3 or higher adverse reactions in the sorafenib group were important factors affecting ICUR.Probabilistic sensitivity analysis showed that tislelizumab had a significant cost-utility advantage when WTP was 3 times GDP,with an economic probability of 81.4％,and the results were robust.Conclusion For the first-line treatment of advanced unresectable hepatocellular carcinoma,tislelizumab has a significant cost-utility advantage over sorafenib.
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ObjectiveTo investigate the safety and efficacy of tyrosine kinase inhibitors combined with immune checkpoint inhibitors in the treatment of patients with Child-Pugh class B unresectable hepatocellular carcinoma （uHCC）. MethodsA total of 96 patients with Child-Pugh class B uHCC who were admitted to Beijing Ditan Hospital， Capital Medical University， from December 31， 2020 to March 30， 2023 were enrolled as subjects， among whom 63 patients receiving lenvatinib combined with programmed death-1 （PD-1） inhibitor were enrolled as L group and 33 patients receiving sorafenib combined with PD-1inhibitor were enrolled as S group. The primary endpoint was objective response rate （ORR）， and secondary endpoints included time to progression （TTP）， overall survival （OS）， toxicity， drug withdrawal rate， and dose adjustment rate. The The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical data between two groups. Survival curves were plotted， and the Kaplan-Meier method was used to calculate the survival rate of patients in both groups， while the Log-rank test was used for comparison between the two groups. The Cox regression model was used to calculate hazard ratio （HR） and its 95% confidence interval （CI） and perform the multivariate analysis of influencing factors for prognosis. ResultsAmong the 96 patients with uHCC， 55 （57.3%） had Child-Pugh class B （7 points） uHCC and 41 （42.7%） had Child-Pugh class B （8—9 points） uHCC. The L group had a significantly higher ORR than the S group （46.0% vs 15.2%， P=0.003）， and there were no significant differences between the L group and the S group in median TTP （6.6 months vs 3.5 months， P=0.48） or OS （13.8 months vs 13.2 months， P=0.95）. There was no significant difference in median TTP between the patients with Child-Pugh class B （7 points） uHCC and those with Child-Pugh class B （8—9 points） uHCC （6.6 months vs 4.8 months， P=0.35）， while there was a significant difference in OS between these two groups of patients （14.5 months vs 8.8 months， P=0.045）. The multivariate analysis showed that ORR was a protective factor for both TTP （HR=0.18， 95%CI： 0.09 — 0.36， P<0.001） and OS （HR=0.20， 95%CI： 0.09 — 0.43， P<0.001）. There were no significant differences between the L group and the S group in the overall incidence rate of adverse reactions （98.4% vs 97.0%） and the incidence rate of grade≥3 adverse reactions （68.3% vs 63.6%）， and there were also no significant differences between the two groups in dose adjustment rate （84.8% vs 70.2%） and drug withdrawal rate （56.1% vs 72.7%）. ConclusionCompared with the regimen of sorafenib combined with PD-1 inhibitor， the regimen of lenvatinib combined with PD-1 inhibitor can improve the ORR of patients with Child-Pugh class B uHCC， with similar prognosis and safety profile between the two groups.
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ObjectiveTo investigate the effects of berbamine hydrochloride on sorafenib resistance in hepatocellular carcinoma cells and the underlying mechanisms. MethodThe sorafenib-resistant cell line SMMC-7721/S was selected by the concentration increment method starting at 1.25 μmol·L-1 sorafenib. Both SMMC-7721 and SMMC-7721/S cells were treated with 0， 2.5， 5， 10， 15， 20 μmol·L-1 sorafenib， and the cell counting kit-8 （CCK-8） assay was employed to determine the half maximal inhibitory concentration （IC50） and calculate the resistance index （RI）. Western blot was conducted to compare the expression of proteins involved in autophagy and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin （PI3K/Akt/mTOR） signaling pathway between SMMC-7721 and SMMC-7721/S cells. Furthermore， SMMC-7721/S cells were treated with 5 μmol·L-1 berbamine hydrochloride alone or in combination with 2.5， 5， 10 μmol·L-1 sorafenib， and the cell growth was assessed by the CCK-8 assay. In addition， SMMC-7721 and SMMC-7721/S cells were treated with 5 μmol·L-1 berbamine hydrochloride alone or in combination with 5 μmol·L-1 sorafenib， and the cell proliferation was examined by the colony formation assay. The immunofluorescence assays with Microtubule-associated protein 1 light chain 3 （LC3） and LysoTracker as probes were employed to assess the lysosomal acidification in SMMC-7721 cells treated with 5 μmol·L-1 berbamine hydrochloride or 0.1 μmol·L-1 autophagy inhibitor bafilomycin A1 （Baf）. Further， the expression of proteins involved in autophagy and PI3K/Akt/mTOR signaling pathway was determined by Western blot and compared between groups. ResultSorafenib showed the IC50 of 9.56 mol·L-1 （P<0.01） and 7.99 mol·L-1 for SMMC-7721/S and SMMC-7721 cells， respectively， at 24 h. The resistance index （RI） of SMMC-7721/S for sorafenib was 1.20 （P<0.01）， which indicated mild resistance. Compared with SMMC-7721 cells， SMMC-7721/S cells exhibited up-regulated expression of p-mTOR， p-Akt， and LC3Ⅱ， down-regulated expression of p62 protein （P<0.01）， and unchanged Akt protein level. CCK-8 and colony formation assays demonstrated that the combination of berbamine hydrochloride and sorafenib exhibited a synergistic effect （Q>1.15）， with berbamine hydrochloride partially reversing the resistance of liver cancer cells to sorafenib. The immunofluorescence detection of LC3 revealed that berbamine hydrochloride and Baf significantly increased LC3 in SMMC-7721 cells. The detection with LysoTracker as the probe showed that berbamine hydrochloride inhibited the acidity of lysosomes in SMMC-7721 cells （P<0.01）， indicating the suppression of autophagy. Berbamine hydrochloride further enhanced the downregulation of p-mTOR and p-Akt protein levels and did not change the Akt protein level in SMMC-7721 cells exposed to sorafenib. Berbamine hydrochloride inhibited the increase in p-mTOR expression， down-regulated the p-Akt protein level， and did not change the total Akt protein level in the SMMC-7721/S cells exposed to sorafenib. ConclusionBerbamine hydrochloride can ameliorate the resistance of liver cancer cells to sorafenib by inhibiting cellular autophagy and the PI3K/Akt/mTOR signaling pathway.
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OBJECTIVE To observe the clinical efficacy and safety of camrelizumab combined with sorafenib in the treatment of advanced liver cancer. METHODS Sixty patients with advanced liver cancer who were treated in our hospital from March 2020 to November 2021 were selected as the study subjects， and then were randomly divided into study group and control group， with 30 cases in each group. The control group was treated with Sorafenib tosylate tablets orally （0.4 g，bid）， and the study group was additionally given Camrelizumab for injection intravenously （200 mg， every 3 weeks） based on the control group； for all patients， the treatment was stopped until disease progression or intolerable side effects occurred. The clinical efficacy， progression-free survival （PFS）， total survival （OS） and 1-year survival rate of the two groups were compared， and the incidence of adverse reactions in two groups， and immune-related adverse reactions in the study group during treatment were recorded. RESULTS The objective remission rate of the study group was significantly higher than the control group （36.7% vs. 13.3%， P＜0.05）， and the median OS and median PFS were significantly longer than the control group （OS： 12.6 months vs. 7.9 months； PFS： 8.2 months vs. 5.3 months， P＜0.05）. There was no significant difference in the 1-year survival rate and the incidence of elevated aspartate aminotransferase and alanine aminotransferase， rash or pruritus， anorexia， diarrhea， fatigue and hypertension between the two groups （P＞0.05）. The adverse events immune-related in the study group mainly included 21 cases of reactive capillary hyperplasia （70.0%）， 6 cases of hypothyroidism （20.0%）， and 1 case of immune-associated pneumonia （3.3%）， which were improved or tolerable after symptomatic treatment. CONCLUSIONS Camrelizumab combined with sorafenib in the treatment of advanced liver cancer can effectively control and delay the disease progression， prolong the survival period of patients， and the adverse reactions can be tolerated.
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ObjectiveSorafenib is a first-line only drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Resistance to sorafenib means that treatment outcomes are often unsatisfactory. Although the mechanism underlying sorafenib resistance remains unclear, resistance may occur through Akt signaling pathway activation in HCC. Dihydrotanshinone (DHT), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has multiple anti-tumor activities and inhibits Akt activation. The effect and mechanism of DHT combined with sorafenib on HCC have not been investigated. In this study, we investigate whether DHT potentiates the anti-cancer activities of sorafenib against HCC. MethodsIn this study, the effects of sorafenib and DHT on the viability, apoptosis and drug sensitivity of Huh7 and HepG2 cells were verified by Cell Counting Kit-8 (CCK-8) and flow cytometry. Akt, P-Akt, Caspase3, GSK-3β, P-GSK-3β, ribosomal protein S6 kinase (S6K), P-S6K, Cyclin D1, Bcl-xl, Bcl-2, and Bax expression levels were analyzed via Western blot. All data were statistically compared using one-way analysis of variance (ANOVA) and Dunnett test. Statistical analysis using SPSS 20.0 statistical software. ResultsDHT inhibit proliferation and promote apoptosis in HCC cells by reducing Akt activation. DHT inhibits the expression and activation of Akt downstream factors, including GSK-3β and S6K, which regulate the apoptotic response and are activated and upregulated by sorafenib treatment. Both sorafenib and DHT downregulate cyclin D1 expression and DHT upregulates Bax expression and downregulates Bcl-2 and Bcl-xl expression. However, sorafenib had little influence on Bcl-2 family protein expression. ConclusionDHT may enhance the proliferation inhibition and apoptosis induction of sorafenib in HCC cells by inhibiting the activation of Akt signaling pathway, thus enhancing the anticancer effect of sorafenib.
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ABSTRACT Differentiated thyroid carcinoma (DTC) accounts for most cases of thyroid cancer, and the heterogeneity of DTC requires that management decisions be taken by a multidisciplinary team involving endocrinologists, head and neck surgeons, nuclear medicine physicians, pathologists, radiologists, radiation oncologists, and medical oncologists. It is important for nonspecialists to recognize and refer patients with DTC who will benefit from a specialized approach. Recent advances in knowledge and changes in management of DTC call for the need to raise awareness on the part of these nonspecialist physicians, including general endocrinologists and medical oncologists at large. We provide an overview of diagnostic and therapeutic principles in DTC, especially those that bear direct implication on day-to-day management of these patients by generalists. Patients with DTC may be broadly categorized as having localized, locally persistent/recurrent, or metastatic disease. Current recommendations for DTC include a three-tiered system that classifies patients with localized disease into low, intermediate, or high risk of persistent or recurrent disease. Risk stratification should be performed at baseline and repeated on an ongoing basis, depending on clinical evolution. One of the overarching goals in the management of DTC is the need to personalize treatment by tailoring its modality and intensity according to ongoing prognostic stratification, evolving knowledge about the disease, and patient characteristics and preference. In metastatic disease that is refractory to radioactive iodine, thyroid tumors are being reclassified into molecular subtypes that better reflect their biological properties and for which molecular alterations can be targeted with specific agents.
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Objective To conduct reevaluation of systematic review/Meta-analysis on the efficacy and safety of transcatheter arteri-al chemoembolization(TACE)combined with sorafenib in the treatment of unresectable hepatocellular carcinoma(HCC).Methods The systematic reviews and Meta-analysis of TACE combined with sorafenib in the treatment of HCC were collected through computer searches on PubMed,Embase,the CochraneLibrary,CNKI and Wanfang data knowledge service platform.The time limit was from data-base inception to August 2022.The experimental group received TACE combined with sorafenib,and the control group received other con-ventional treatments.After screening the literature and extracting the data,PRISMA statement was adopted to evaluate the quality of the included reports,AMSTAR 2scale was used for methodological quality evaluation,and GRADE tool was used for outcome indicator and evidence quality evaluation.Results A total of 9 literatures were included,including 43 outcome indicators.The PRISMA score was 20.5-25.5,including 7 articles of high quality and 2 articles of moderate quality.The results of AMSTAR 2 quality evaluation show that all the literatures were of extremely low quality,and the key items with the most problems were item 2 and item 7.The results of GRADE evaluation showed that there were 4 high quality indicators,15medium quality indicators,21 low quality indicators and 3 unevaluable indi-cators.The main factor leading to degradation was bias risk,followed by inconsistency.In terms of curative effect,compared with the con-trol group,the 1-year survival rate,time to progression,objective response rate and disease control rate of patients in the experimental group were significantly improved.However,the incidence of adverse reactions(diarrhea,hand and foot syndrome,hypertension)in the control group was significantly better than those in the experimental group.Conclusion The methodology quality and evidence quality of systematic review/Meta-analysis related to TACE combined with sorafenib in the treatment of HCC is poor,and the standardization still needs to be further improved.
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Hepatocellular carcinoma (HCC) is one of the most deadly malignancies in the world, with strong invasiveness, low cure rate, high metastasis rate and poor prognosis. Sorafenib is the most important and effective first-line drug for the treatment of advanced hepatocellular carcinoma, but its clinical efficacy is severely limited by primary and acquired drug resistance. Mi-crornas ( micrornas) are small non-coding Rnas that play a key regulatory role in the occurrence and development of hepatocellular carcinoma and the progression of sorafenib resistance. This paper summarizes the role of micrornas in the initiation and development of sorafenib resistance in hepatocellular carcinoma, in order to further understand the mechanism of sorafenib anti-hep-atocellular carcinoma, and to provide valuable theoretical basis for clinical targeted therapy and prognosis improvement in hepatocellular carcinoma.
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AIM: To explore the pharmacokinetic interactions between sorafenib and dapagliflozin in rats and to provide some theoretical basis for the rational clinical use of the two drugs. METHODS: An ultra -performance liquid chromatography-tandem mass spectrometry (UPLC / MS / MS) method was developed for the simultaneous determination of sorafenib and dapagliflozin. Male SD rats were randomly divided into 5 groups (6 rats in each group), including 100 mg / kg sorafenib group, 0.5 mg / kg dapagliflozin group, 1 mg / kg dapagliflozin group, and 100 mg/kg sorafenib combined with 0.5 mg/kg dapagliflozin group and 100 mg/kg sorafenib combined with 1 mg / kg dapagliflozin group, for sorafenib and dapagliflozin drug interaction study. All samples were analyzed using a validated UPLC/ MS/MS method, and the main pharmacokinetic parameters were calculated by compartment model. RESULTS: 1 mg/kg dapagliflozin increased the C
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Objective:To investigate the clinical effect of stereotactic radiation therapy combined with sorafenib in the treatment of primary hepatic cancer (PHC).Methods:Ninety-two PHC patients admitted to Cancer Hospital of China Medical University from January 2017 to May 2018 were selected and divided into the observation group and the control group according to the random number table method, with 46 cases in each group. The control group was treated with stereotactic radiation therapy, and the observation group was treated with sorafenib on the basis of the control group. Clinical efficacy and incidence of adverse reactions in the two groups were compared; the scores of Karnofsky performance scale (KPS) and the levels of serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hypoxia-inducing factor (HIF-1α), soluble interleukin-2 receptor (sIL-2R), transforming growth factor (TGF-β1) and alpha-fetoprotein (AFP) before and after the treatment between the two groups were compared. The overall survival (OS) of patients in both groups was recorded after 36 months of follow-up.Results:The total effective rate in the observation group was higher than that in the control group: 84.78%(39/46) vs. 65.22%(30/46), there was statistical difference ( χ2 = 4.70, P<0.05). After the treatment, the score of KPS in the observation group was higher than that in the control group: (85.06 ± 7.19) scores vs. (71.16 ± 7.08) scores; the levels of VEGF, bFGF, HIF-1α, AFP, TGF-β1, sIL-2R in the observation group were lower than those in the control group: (189.52 ± 31.47) ng/L vs. (235.81 ± 35.45) ng/L, (3.89 ± 0.97) ng/L vs. (6.74 ± 1.85) ng/L, (50.17 ± 6.09) ng/L vs. (53.07 ± 6.28) ng/L, (85.76 ± 14.09) μg/L vs. (131.51 ± 18.74) μg/L, (81.07 ± 12.96) μg/L vs. (106.58 ± 15.07) μg/L, (311.58 ± 74.81) kU/L vs. (405.97 ± 85.74) kU/L, there were statistical differences ( P<0.05). The results of 36 months follow-up showed that the 1-year and 3-year OS in the observation group were higher than those in the control group: 69.57% (32/46) vs. 58.70% (27/46), 43.47% (20/46) vs. 28.26 %(13/46), there were significant differences ( χ2 = 4.78, 3.94, P<0.05). Conclusions:Stereotactic radiation therapy combined with sorafenib can effectively improve the efficacy of PHC patients, reduce the expression of VEGF and bFGF, effectively inhibit tumor growth, but also prolong the survival time of patients, with both safety and high effectiveness, and good use value.
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Objective:To investigate the synergistic effects and molecular mechanisms of dihydroartemisinin(DHA) and sorafenib(SOR) in inducing ferroptosis in anaplastic thyroid cancer(ATC) cells.Methods:CCK-8 and flow cytometry assays were performed to detect the effects of DHA and SOR on the proliferation and ferroptosis of ATC cells(CAL-62). Real-time fluorescence quantitative PCR and Western blotting assays were performed to detect the expressions of ferroptosis-related genes glutathione peroxidase 4(GPX4), solute carrier family 7 member 11 gene(SCL7A11), lipoxygenase-15(LOX-15), and p53. The levels of iron death intermediate metabolites including lactate dehydrogenase(LDH), glutathione(GSH), malondialdehyde(MDA), ferrous ion(Fe 2+ ), nitric oxide(NO), and reactive oxygen species(ROS)were measured by corresponding assay kits. The corresponding inhibition of DHA and SOR on ATC in vivo was analyzed in a tumor model in nude mice. Results:Compared with the control group, DHA, SOR, and DHA+ SOR treatment significantly inhibited cell proliferation and apoptosis in a dose-dependent manner( P<0.001), with increased LDH, Fe 2+, MDA, and ROS contents and reduced GSH activity( P<0.001), which were promoted by ferrous sulfate(FeSO 4)and reversed by ferroptosis inhibitor-1. Compared with the control group and the drug monotherapy group, 15-LOX-2 and p53 expressions were upregulated in DHA+ SOR group while GPX4 and SCL7A11 expressions were decreased( P<0.001), without significant difference in 15-LOX-1 protein content. In addition, NO level was significantly increased in DHA+ SOR group( P<0.001). DHA and SOR inhibited tumor growth of ATC in vivo. Conclusion:DHA and SOR synergistically induced ferroptosis via upregulating the expression of 15-LOX-2 gene and inhibiting NO synthesis in ATC cells.
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The extracts of Platycladus orientalis (L.) Franco leaves have shown promising anti-cancer, anti-oxidant and anti-inflammatory potency with the traditional knowledge of healing HPV associated warts. The purpose of this research is to assess the synergistic activity of sorafenib and Platycladus orientalis (L) leaf extraction on cervical cancer cells. The cytotoxicity efficiency of different concentrations of Sorafenib and ethanol extract of Platycladus orientalis (L.) leaves were tested on HeLa cells by MTT and Trypan blue assays. The synergistic effect of the IC50 concentrations of Sorafenib and Platycladus orientalis (L.) on HeLa cell by MTT assay, and mRNA expression levels of tumor suppressor tazarotene-induced gene 3 (TIG3), proliferating cell nuclear antigen (PCNA) gene and apoptosis modulator (Bcl-2) gene by RT-PCR were evaluated with individual treatments. Combination treatment showed a relatively more expression of TIG3 and less expression of Bcl-2 and PCNA was observed. Growth factor-induced MAPKP activation was arrested by compound combination treatment, which and suppression of proliferation-induced apoptosis of cervical cancer cells. Based on the our results, the combination of sorafenib and crude leaf extract from Platycladus orientalis (L.) can effectively suppress cervical cancer cell growth, thereby providing an interesting rationale for further clinical trials and in-vivo studies.
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Uterine Cervical Neoplasms , SorafenibABSTRACT
Hepatocellular carcinoma (HCC) is a malignant tumor with high incidence rate and mortality worldwide. However, most patients are not suitable for radical treatment at the time of first diagnosis. As one of the important schemes for the treatment of HCC, one of the most representative drug is Sorafenib, which has certain survival benefits for HCC patients at different stages. However, the drug resistance of HCC to Sorafenib greatly limits its efficacy. So far, people have found that some natural substances, experimental agents and biological macromolecules can reverse the drug resistance of HCC to Sorafenib through tumor cell microenvironment, metabolism and other mechanisms. This article will summarize the above substances and their mechanism in order to provide research ideas for the improvement of Sorafenib′s treatment program.
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Objective To investigate the value of alpha-fetoprotein (AFP) response in evaluating the clinical efficacy and safety of sorafenib combined with camrelizumab in the treatment of advanced hepatocellular carcinoma (HCC). Methods Clinical data were collected from 48 patients with advanced HCC who were treated with sorafenib combined with camrelizumab in The First Affiliated Hospital of Xinjiang Medical University from September 2020 to February 2022, and according to the level of AFP response after treatment, they were divided into response group with 32 patients (AFP after 6-8 months of treatment was reduced by more than 20% compared with baseline AFP) and non-response group with 16 patients (AFP after 6-8 months of treatment was reduced by less than 20% compared with baseline AFP). The Mann-Whitney U test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data between groups. Survival curves were plotted, and univariate and multivariate Cox regression analyses were used to investigate the independent risk factors for overall survival (OS). Progression free survival (PFS) time, OS time, and treatment outcome were compared between the two groups. Results No patient achieved clinical remission in either group. Compared with the non-response group, the response group had significantly higher objective response rate (21.88% vs 0, χ 2 =2.530, P =0.112) and disease control rate (84.38% vs 43.75%, χ 2 =6.668, P =0.010). Compared with the non-response group, the response group had longer PFS time (9.9 months vs 6.8 months) and OS time (13.8 months vs 11.1 months). Early non-response of AFP (hazard ratio [ HR ]=2.624, 95% confidence interval [ CI ]: 1.097-6.277, P =0.030) and extrahepatic metastasis ( HR =0.392, 95% CI : 0.157-0.978, P =0.045) were independently associated with a shorter PFS time. No adverse event leading to drug withdrawal was observed in the study. Conclusion Early AFP response has a high clinical value in predicting the efficacy of sorafenib combined with camrelizumab in the treatment of advanced HCC and the prognosis of such patients.
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Being the most common solid malignant tumor in the digestive system and the third leading cause of cancer-related death worldwide， hepatocellular carcinoma （HCC） is characterized by insidious onset， early recurrence/metastasis and poor prognosis. With the advantages of targeted precision， high specificity， minimal drug resistance， remarkable therapeutic efficacy and fewer side effects， molecular targeted drugs have become the hotspot and focus of tumor therapy research in recent years. As more is learned about the mechanism and clinical efficacy， some molecular targeted drugs have been recommended by HCC treatment guidelines. This paper reviewed the mechanism of HCC targeted therapy， molecular targeted drugs， relevant therapeutic protocols and outcomes so as to provide reference and evidence for subsequent research.
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【Objective】 To analyze the correlation between the expressions of CD10,CA9 and CD133 and the prognosis of patients with metastatic renal clear cell carcinoma (mccRCC) treated with sorafenib or sunitinib. 【Methods】 A total of 80 mccRCC patients who received sorafenib or sunitinib as first-line therapy were retrospectively enrolled. Immunohistochemical staining (IHC) was performed for CD10,CA9 and CD133 in tumor tissue samples to analyze the correlation between the expression of each marker and clinicopathologic variables. Univariate and multivariate Cox proportional risk models were used to analyze prognostic factors of progression free survival (PFS) and overall survival (OS),and Kaplan-Meier survival analysis was performed for CA9 expression and PFS,OS in the treatment subgroups. 【Results】 Altogether 37 patients (46.25%) had PFS,and the median PFS (mPFS) was 24.9 months (95%CI:16.5-33.2 months),while 55 patients (68.75%) died and the median OS (mOS) was 44.2 months (95%CI:14.6-73.7). Low expression of CD10 was correlated with high Fuhrman grade (χ2=6.241,P=0.012),lymph node metastasis (χ2=5.952,P=0.015),and the number of metastatic organs ≥2 (χ2=8.205,P=0.004). Univariate analysis showed that Fuhrman grade,number of metastatic organs and lymph node metastasis were the prognostic factors of PFS (P<0.05),while the number of metastatic organs,lymph node metastasis and CA9 expression were the prognostic factors of OS (P<0.05). Multivariate analysis showed that Fuhrman grade was an independent factor of PFS (HR=2.457,95%CI:1.126-5.365,P=0.024),and the number of metastatic organs was an independent prognostic factor of OS (HR=1.857,95%CI:1.048-3.290,P=0.034). Survival analysis in subgroups showed that high CA9 expression in the sorafenib group was associated with longer OS (HR=0.401,95%CI:0.204-0.787,P=0.008). 【Conclusion】 Low expression of CA9 is an non-independent risk factor for OS,while CD10 and CD133 cannot be used as prognostic factors for mccRCC patients. Since mccRCC patients with low CA9 expression have less survival benefit from sorafenib and sunitinib,they can choose target therapy combined with immunotherapy or dual immunotherapy according to the guidelines to improve prognosis.
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【Objective】 To explore the therapeutic effects of lactate dehydrogenase A (LDHA) inhibitor and targeted drugs on fumarate-hydratase-deficient renal cell carcinoma (FH-d RCC). 【Methods】 RNA-sequencing was used to detect the mRNA expression in FH-d RCC tissues, which was further validated with real-time fluorescence quantitative PCR and immunohistochemistry. Human-derived FH-d RCC cell line UOK262 and murine-derived FH-d RCC cell line FH1-/-CL19 (CL19) were treated with LDHA inhibitor [(R)-GNE-140] and listed kidney cancer targeted drugs (Axitinib, Cabozantinib, Sunitinib, Sorafenib, Pazopanib, Everolimus) respectively, and then treated with LHDA inhibitor in combination with the targeted drugs to observe the alteration of cell proliferation. The combination index (CI) of different dose groups of the combination drugs were analyzed with CompuSyn software to determine the optimal combination regimen. 【Results】 LDHA inhibitor and targeted drugs, including Cabozantinib, Sorafenib and Sunitinib, had a significant inhibitory effect on the proliferation of FH-d RCC cells, and the combination of Cabozantinib and Sorafenib or Pazopanib had a significant anti-tumor effect. 【Conclusion】 LDHA inhibitor combined with targeted drugs can significantly inhibit the growth of FH-d RCC cells, indicating that LDHA may be a potential therapeutic target of FH-d RCC.
ABSTRACT
Objective: To investigate the effect and possible mechanism of Y-box-binding protein 1 (YB-1) on sorafenib resistance in hepatoma cells. Methods: Lentiviral vectors with YB-1 overexpression and knockdown were constructed, respectively, to stimulate human hepatoma cell lines (HepG2 and Huh7) alone or in combination with sorafenib.The overexpression part of the experiment was divided into four groups: overexpression control group (Lv-NC), YB-1 overexpression group (Lv-YB-1), overexpression control combined with sorafenib resistance group (Lv-NC+sorafenib), YB-1 overexpression combined with sorafenib resistance group (Lv-YB-1 + sorafenib). The knockdown part of the experiment was also divided into four groups: knockdown control group (Lv-shNC), YB-1 knockdown group (Lv-shYB-1), knockdown control combined with sorafenib resistance group (Lv-shNC + sorafenib), YB-1 knockdown combined with sorafenib resistance group (Lv-shYB-1 + sorafenib). The occurrence of cell apoptosis was detected by TUNEL. The protein expression levels of phosphorylated (p)-ERK and ERK, key proteins in the extracellular regulatory protein kinase (ERK) signaling pathway, were detected by Western blot and quantified by ImageJ software. Subcutaneous tumorigenesis experiments were performed in nude mice. The effect of YB-1 on the efficacy of sorafenib was verified in vivo. The comparison between the two sets of data was carried out by an independent sample t-test. One-way ANOVA was used for comparisons between the three groups of data above. Results: Sorafenib had accelerated the occurrence of apoptosis in hepatoma cells, while YB-1 overexpression had inhibited cell apoptosis, and at the same time also inhibited the apoptosis-accelerating impact of sorafenib. On the contrary, YB-1 knockdown accelerated cell apoptosis and amplified the induction effect of sorafenib on apoptosis. Furthermore, sorafenib resistance had down-regulated p-ERK levels (HepG2: Lv-NC 0.685 ± 0.143, Lv-NC + sorafenib 0.315 ± 0.168, P < 0.05; Huh7: Lv-NC 0.576 ± 0.078, Lv-NC + sorafenib 0.150 ± 0.131, P < 0.01), whereas YB-1 overexpression had inhibited sorafenib resistance p-ERK reduction (HepG2: Lv-NC + sorafenib 0.315 ± 0.168, Lv-YB-1 + sorafenib 0.688 ± 0.042, P < 0.05; Huh7: Lv-NC + sorafenib 0.150 ± 0.131, Lv-YB-1 + sorafenib 0.553 ± 0.041, P < 0.05). YB-1 knockdown further increased sorafenib-induced p-ERK downregulation (HepG2: Lv-shNC + sorafenib 0.911 ± 0.252, Lv-shYB-1 + sorafenib 0.500 ± 0.201, P < 0.05; Huh7: Lv-shNC + sorafenib 0.577 ± 0.082, Lv-shYB-1 + sorafenib 0.350 ± 0.143, P < 0.05), which was further verified in naked mice (Lv-shNC + sorafenib 0.812 ± 0.279, Lv-shYB-1 + sorafenib 0.352 ± 0.109, P < 0.05). Conclusion: YB-1 mediates the occurrence of sorafenib resistance via the ERK signaling pathway in hepatoma cells.