BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase...BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.展开更多
Transarterial chemoembolization(TACE)has been widely introduced to treat hepatocellular carcinoma(HCC)especially for unresectable patients for decades.However,TACE evokes an angiogenic response due to the secretion of...Transarterial chemoembolization(TACE)has been widely introduced to treat hepatocellular carcinoma(HCC)especially for unresectable patients for decades.However,TACE evokes an angiogenic response due to the secretion of vascular endothelial growth factor(VEGF),resulting in the formation of new blood vessels and eventually tumor recurrence.Thus,we aimed to develop regorafenib(REGO)-loaded poly(lactide-co-glycolide)(PLGA)microspheres that enabled localized and sustained drug delivery to limit proangiogenic responses following TACE in HCC treatment.REGO-loaded PLGA microspheres were prepared using the emulsion-solvent evaporation/extraction method,in which DMF was selected as an organic phase co-solvent.Accordingly,we optimized the proportion of DMF,which the optimal ratio to DCM was 1:9(v/v).After preparation,the microspheres provided high drug loading capacity of 28.6%,high loading efficiency of 91.5%,and the average particle size of 149μm for TACE.IR spectra and XRD were applied to confirming sufficient REGO entrapment.The in vitro release profiles demonstrated sustained drug release of microspheres for more than 30 d To confirm the role of REGO-loaded microspheres in TACE,the cell cytotoxic activity on HepG2 cells and anti-angiogenic effects in HUVECs Tube-formation assay were studied in combination with miriplatin.Moreover,the microspheres indicated the potential of antagonizing miriplatin resistance of HepG2 cells in vitro.Pharmacokinetics preliminary studies exhibited that REGO could be sustainably released from microspheres for more than 30d after TACE in vivo.In vivo anti-tumor efficacy was further determined in HepG2 xenograft tumor mouse model,demonstrating that REGO microspheres could improve the antitumor efficacy of miriplatin remarkably compared with miriplatin monotherapy.In conclusion,the obtained REGO microspheres demonstrated promising therapeutic effects against HCC when combined with TACE.展开更多
AIM:To evaluate the inhibitory effects of regorafenib(BAY 73-4506),a multikinase inhibitor,on corneal neovascularization(NV).METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g,were used.Corneal NV was in...AIM:To evaluate the inhibitory effects of regorafenib(BAY 73-4506),a multikinase inhibitor,on corneal neovascularization(NV).METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g,were used.Corneal NV was induced by NaOH in the left eyes of each rat.Following the establishment of alkali burn,the animals were randomized into five groups according to topical treatment.Group 1(n=6)received 0.9%NaCl,Group 2(n=6)received dimethyl sulfoxide,Group 3(n=6)received regorafenib 1 mg/mL,Group 4(n=6)received bevacizumab 5 mg/mL and Group 5(n=6)received 0.1%dexamethasone phosphate.On the 7d,the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea’s total area using computer-imaging analysis.The corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by immunostaining.RESULTS:A statistically significant difference in the percent area of corneal NV was found among the groups(P【0.001).Although the Group 5 had the smallest percent area of corneal NV,there was no difference among Groups 3,4 and 5(P】0.005).There was a statistically significant difference among the groups in apoptotic cell density(P=0.002).The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups(P【0.05).The staining intensity of epithelial and endothelial vascular endothelial growth factor was significantly weaker in Groups 3,4 and 5 thanin Groups 1 and 2.CONCLUSION:Topical administration of regorafenib 1mg/mL is partly effective for preventing alkali-induced corneal NV in rats.展开更多
BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma(HCC)is a common situation.The only therapeutic options in France are two broadspectrum tyrosine kinase inhibitors(TKIs),regorafenib(REG...BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma(HCC)is a common situation.The only therapeutic options in France are two broadspectrum tyrosine kinase inhibitors(TKIs),regorafenib(REG)and cabozantinib(CBZ),but no comparative real-life studies are available.AIM To evaluate the progression-free survival(PFS)of patients treated with REG or CBZ,we investigated the disease control rate(DCR),overall survival(OS),and safety of both drugs.To identify the variables associated with disease progression over time.METHODS A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers(Avignon,Marseille,and Nice)between January 2017 and March 2021 using propensity score matching.PFS and OS were assessed using the Kaplan-Meier method.Multivariate analysis(MA)of progression risk factors over time was performed in matched-pair groups.RESULTS Fifty-eight patients 68(62-74)years old with HCC,Barcelona clinic liver cancer(BCLC)B/C(86%),Child-Pugh(CP)-A/B(24%)received REG for 3.4(1.4-10.5)mo as second-line therapy.Twentyeight patients 68(60-73)years,BCLC B/C(75%),CP-A/B(25%)received CBZ for 3.7(1.8-4.9)mo after first-line treatment with sorafenib[3(2-4)(CBZ)vs 4(2.9-11.8)mo(REG),P=0.0226].Twenty percent of patients received third-line therapy.After matching,PFS and DCR were not significantly different after a median follow-up of 6.2(2.7-11.7)mo(REG)vs 5.2(4-7.2)mo(CBZ),P=0.6925.There was no difference in grade 3/4 toxicities,dose reductions,or interruptions.The OS of CP-A patients was 8.3(5.2-24.8)vs 4.9(1.6-11.7)mo(CP-B),P=0.0468.The MA of risk factors for progression over time identified C-reactive protein(CRP)>10 mg/L,neutrophil-to-lymphocyte ratio(NLR)>3,and aspartate aminotransferase(AST)>45 IU as predictive factors.CONCLUSION This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC.Elevated levels of inflammatory markers(CRP and NLR)and AST were associated with non-control of TKIs over time.A 2-mo online progression risk calculation is proposed.展开更多
BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of ...BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal capillary proliferation(n=1),transaminase elevation(n=1),and hand-foot syndrome(n=2).No grade 4 or higher toxicity was observed.CONCLUSION Regorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC.The PLR might be a prediction of the patient response to this therapy.展开更多
Objective The objective of this study was to investigate the inhibitory effects of sorafenib and regorafenib on the growth of hepatocellular carcinoma(HCC)using a subcutaneous transplantation tumor model in nude mice ...Objective The objective of this study was to investigate the inhibitory effects of sorafenib and regorafenib on the growth of hepatocellular carcinoma(HCC)using a subcutaneous transplantation tumor model in nude mice and exploring the effects of sorafenib and regorafenib on the expression of hypoxia-inducible factor(HIF)-1α,HIF-2α,and HIF-1βin HCC tissues collected from HCC-transplanted nude mice.Methods HepG2 cells were inoculated intradermally into nude mice.The mice were randomly assigned to either sorafenib treatment(100 mg/kg),regorafenib treatment(20 mg/kg),or solvent control group(dimethylsulfoxide)(n=8 per group)and received once-daily treatment for 14 days.The tumor volumes were recorded every 3 days after the initiation of treatment.The expression levels of HIF-1α,HIF-1β,HIF-2α,and SART1 in the HCC tissues were examined via quantitative real-time PCR(qRT-PCR)analysis and Western blotting.Results The tumors in the sorafenib and regorafenib treatment groups grew slower and smaller than did the tumors in the solvent control group.qPCR analysis and western blotting demonstrated that the mRNA and protein expressions of HIF-1αand HIF-1βwere down-regulated.The expression of HIF-2αand SART1 was up-regulated in the sorafenib treatment group(P<0.05);meanwhile,the expression of HIF-1αand HIF-1βwas up-regulated,and that of HIF-2αand SART1 was down-regulated in the regorafenib treatment group(P<0.05).Conclusion The expression of hypoxia-associated factor is up-regulated by sorafenib and down-regulated by regorafenib,which may induce the different effects of sorafenib on the expression of HIFs.展开更多
Background: Colorectal cancer is one of the most common cancer types, frequently metastasizing into the lungs. Treatment options have been vastly improved over the last years. With the increasing use of targeted thera...Background: Colorectal cancer is one of the most common cancer types, frequently metastasizing into the lungs. Treatment options have been vastly improved over the last years. With the increasing use of targeted therapies, novel and rare adverse effects can be seen. Case Presentation: A 43-year-old woman presented in our oncology department with chest pain and dyspnea. The patient was diagnosed with colorectal cancer seven years earlier and had received chemoradiation, surgery, and multiple chemotherapies before she was started on regorafenib because of progressive pulmonary metastases. Computed tomography scans demonstrated cavitation of former nodular bilateral pulmonary metastases. After drainage and resolution of the right-sided pneumothorax, the patient returned eleven days later with recurrent symptoms caused by left-sided tension pneumothorax. Video-assisted thoracoscopy and bilateral pleurodeses were performed. Persistent air leaks with severe pain and pulmonary infiltrates led to the death of the patient. Conclusions: This case demonstrates the efficacy of oral antiangiogenetic therapy in advanced metastatic colorectal cancer. Nevertheless, it also depicts an important potential side effect by transforming multiple solid lung metastases into cavitations which led to recurrent pneumothoraces. Special attention should be paid to this phenomenon as treatment of these complications can be challenging.展开更多
Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a m...Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a monotherapy.Combining regorafenib with PD-1 inhibitor may improve efficacy and survival outcomes for patients.This retrospective analysis was conducted to explore its efficacy and safety,providing reference experience for better application of this combination therapy.Methods:This retrospective single-center study evaluated the efficacy and safety of combining regorafenib with PD-1 blockade for patients with HCC.Efficacy was evaluated according to the RECIST 1.1 evaluation criteria.Safety was assessed using CTCAE 4.0.Data was analyzed to compare survival status in different subgroups.Results:Generally,there were 76 patients with HCC elected to receive the regorafenib plus PD-1 blockade treatment during the study period.The objective response rate was 21.1%(n?16),and the disease control rate was 56.6%(n?43).Median progression-free survival(PFS)was 6.8 months,and median overall survival had not yet been reached.All patients suffered of at least 1 adverse event.Grade3 adverse events occurred in 31.6%of patients(n?24),with the most common being hand-foot syndrome,decreased appetite,and abdominal distension.Subgroup analyses showed no significant differences in PFS based on cirrhosis status or previous treatment lines.Conclusion:With manageable safety,regorafenib combined PD-1 inhibitor could bring survival benefits for advanced HCC who have received systemic treatment.Further,the Cox analysis showed that HBV infection,metastasis,etc.did not have significant effects on the survival benefits.展开更多
BACKGROUND Gastrointestinal stromal tumors(GISTs)are caused by mutations in the KIT and platelet derived growth factor receptor alpha genes in approximately 90%of cases.A minority of wild-type GISTs are associated wit...BACKGROUND Gastrointestinal stromal tumors(GISTs)are caused by mutations in the KIT and platelet derived growth factor receptor alpha genes in approximately 90%of cases.A minority of wild-type GISTs are associated with neurofibromatosis type 1(NF1),an autosomal dominant genetic disease resulting from pathogenic mutations in the NF1 gene,which encodes the neurofibromin protein.NF1 patients often exhibit multi-system involvement,with café-au-lait macules and neurofibromas being characteristic symptoms.GISTs are a rare complication of NF1,with the tumors most frequently occurring in the small intestine(90%of cases),while occurrences in the stomach are rare.CASE SUMMARY A 51-year-old woman presented to the emergency department with complaints of dizziness,fatigue,chest tightness,and dark stools.Initial examination revealed a red blood cell count of 1.99×1012/L and a hemoglobin level of 43 g/L.She underwent blood transfusions and fluid replacement to stabilize her condition.Further investigations identified typical café-au-lait macules on her trunk,limbs,and face,along with neurofibromas.Endoscopy showed coffee-colored fluid in the gastric cavity,a large submucosal elevation with an exudative covering,and ulcer formation on the gastric fundus.Exploratory laparoscopy confirmed the tumor’s origin in the gastric fundus,and resection of the giant GIST was performed.Pathological analysis revealed a necrotic GIST measuring 18 cm×14 cm,classified as high-risk,with approximately 5 mitotic figures per 10 high-power fields and no tumor at the margins.Immunohistochemistry results were CD117(+),delay of germination 1(+),CD34(+),and succinate dehydrogenase complex iron sulfur subunit B intact expression.Genetic testing using next-generation sequencing confirmed an NF1 gene mutation.The patient underwent successful tumor resection and was discharged home with postoperative regorafenib therapy.A follow-up at one year showed no recurrence.CONCLUSION Given the diversity of clinical symptoms associated with NF1 and the complexity of NF1-related GISTs,surgical resection with complete tumor removal remains the preferred treatment option.However,the absence of a standardized treatment protocol for adjuvant therapy presents numerous challenges for clinicians.展开更多
文摘BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.
基金the National Natural Science Foundation of China(81872819 and 81573379)Natural Science Foundation of Jiangsu Province(BK20171390)+2 种基金supported by"Double First-Class"University project(CPU2018GY26)the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(SKLNMZZCX201816)the financial support from Development Funds for Priority Academic Programs in Jiangsu Higher Education Institutions。
文摘Transarterial chemoembolization(TACE)has been widely introduced to treat hepatocellular carcinoma(HCC)especially for unresectable patients for decades.However,TACE evokes an angiogenic response due to the secretion of vascular endothelial growth factor(VEGF),resulting in the formation of new blood vessels and eventually tumor recurrence.Thus,we aimed to develop regorafenib(REGO)-loaded poly(lactide-co-glycolide)(PLGA)microspheres that enabled localized and sustained drug delivery to limit proangiogenic responses following TACE in HCC treatment.REGO-loaded PLGA microspheres were prepared using the emulsion-solvent evaporation/extraction method,in which DMF was selected as an organic phase co-solvent.Accordingly,we optimized the proportion of DMF,which the optimal ratio to DCM was 1:9(v/v).After preparation,the microspheres provided high drug loading capacity of 28.6%,high loading efficiency of 91.5%,and the average particle size of 149μm for TACE.IR spectra and XRD were applied to confirming sufficient REGO entrapment.The in vitro release profiles demonstrated sustained drug release of microspheres for more than 30 d To confirm the role of REGO-loaded microspheres in TACE,the cell cytotoxic activity on HepG2 cells and anti-angiogenic effects in HUVECs Tube-formation assay were studied in combination with miriplatin.Moreover,the microspheres indicated the potential of antagonizing miriplatin resistance of HepG2 cells in vitro.Pharmacokinetics preliminary studies exhibited that REGO could be sustainably released from microspheres for more than 30d after TACE in vivo.In vivo anti-tumor efficacy was further determined in HepG2 xenograft tumor mouse model,demonstrating that REGO microspheres could improve the antitumor efficacy of miriplatin remarkably compared with miriplatin monotherapy.In conclusion,the obtained REGO microspheres demonstrated promising therapeutic effects against HCC when combined with TACE.
文摘AIM:To evaluate the inhibitory effects of regorafenib(BAY 73-4506),a multikinase inhibitor,on corneal neovascularization(NV).METHODS:Thirty adult male Sprague-Dawley rats weighing 250-300 g,were used.Corneal NV was induced by NaOH in the left eyes of each rat.Following the establishment of alkali burn,the animals were randomized into five groups according to topical treatment.Group 1(n=6)received 0.9%NaCl,Group 2(n=6)received dimethyl sulfoxide,Group 3(n=6)received regorafenib 1 mg/mL,Group 4(n=6)received bevacizumab 5 mg/mL and Group 5(n=6)received 0.1%dexamethasone phosphate.On the 7d,the corneal surface covered with neovascular vessels was measured on photographs as the percentage of the cornea’s total area using computer-imaging analysis.The corneas obtained from rats were semiquantitatively evaluated for caspase-3 and vascular endothelial growth factor by immunostaining.RESULTS:A statistically significant difference in the percent area of corneal NV was found among the groups(P【0.001).Although the Group 5 had the smallest percent area of corneal NV,there was no difference among Groups 3,4 and 5(P】0.005).There was a statistically significant difference among the groups in apoptotic cell density(P=0.002).The staining intensity of vascular endothelial growth factor in the epithelial and endothelial layers of cornea was significantly different among the groups(P【0.05).The staining intensity of epithelial and endothelial vascular endothelial growth factor was significantly weaker in Groups 3,4 and 5 thanin Groups 1 and 2.CONCLUSION:Topical administration of regorafenib 1mg/mL is partly effective for preventing alkali-induced corneal NV in rats.
文摘BACKGROUND Starting a second-line systemic treatment for hepatocellular carcinoma(HCC)is a common situation.The only therapeutic options in France are two broadspectrum tyrosine kinase inhibitors(TKIs),regorafenib(REG)and cabozantinib(CBZ),but no comparative real-life studies are available.AIM To evaluate the progression-free survival(PFS)of patients treated with REG or CBZ,we investigated the disease control rate(DCR),overall survival(OS),and safety of both drugs.To identify the variables associated with disease progression over time.METHODS A retrospective multicenter study was performed on the clinical data of patients attending one of three referral centers(Avignon,Marseille,and Nice)between January 2017 and March 2021 using propensity score matching.PFS and OS were assessed using the Kaplan-Meier method.Multivariate analysis(MA)of progression risk factors over time was performed in matched-pair groups.RESULTS Fifty-eight patients 68(62-74)years old with HCC,Barcelona clinic liver cancer(BCLC)B/C(86%),Child-Pugh(CP)-A/B(24%)received REG for 3.4(1.4-10.5)mo as second-line therapy.Twentyeight patients 68(60-73)years,BCLC B/C(75%),CP-A/B(25%)received CBZ for 3.7(1.8-4.9)mo after first-line treatment with sorafenib[3(2-4)(CBZ)vs 4(2.9-11.8)mo(REG),P=0.0226].Twenty percent of patients received third-line therapy.After matching,PFS and DCR were not significantly different after a median follow-up of 6.2(2.7-11.7)mo(REG)vs 5.2(4-7.2)mo(CBZ),P=0.6925.There was no difference in grade 3/4 toxicities,dose reductions,or interruptions.The OS of CP-A patients was 8.3(5.2-24.8)vs 4.9(1.6-11.7)mo(CP-B),P=0.0468.The MA of risk factors for progression over time identified C-reactive protein(CRP)>10 mg/L,neutrophil-to-lymphocyte ratio(NLR)>3,and aspartate aminotransferase(AST)>45 IU as predictive factors.CONCLUSION This multicenter indirect comparative study found no significant difference in PFS between REG and CBZ as second-line therapy for advanced HCC.Elevated levels of inflammatory markers(CRP and NLR)and AST were associated with non-control of TKIs over time.A 2-mo online progression risk calculation is proposed.
基金Supported by the Henan Provincial Department of Science and Technology,No. 212102310047
文摘BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal capillary proliferation(n=1),transaminase elevation(n=1),and hand-foot syndrome(n=2).No grade 4 or higher toxicity was observed.CONCLUSION Regorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC.The PLR might be a prediction of the patient response to this therapy.
文摘Objective The objective of this study was to investigate the inhibitory effects of sorafenib and regorafenib on the growth of hepatocellular carcinoma(HCC)using a subcutaneous transplantation tumor model in nude mice and exploring the effects of sorafenib and regorafenib on the expression of hypoxia-inducible factor(HIF)-1α,HIF-2α,and HIF-1βin HCC tissues collected from HCC-transplanted nude mice.Methods HepG2 cells were inoculated intradermally into nude mice.The mice were randomly assigned to either sorafenib treatment(100 mg/kg),regorafenib treatment(20 mg/kg),or solvent control group(dimethylsulfoxide)(n=8 per group)and received once-daily treatment for 14 days.The tumor volumes were recorded every 3 days after the initiation of treatment.The expression levels of HIF-1α,HIF-1β,HIF-2α,and SART1 in the HCC tissues were examined via quantitative real-time PCR(qRT-PCR)analysis and Western blotting.Results The tumors in the sorafenib and regorafenib treatment groups grew slower and smaller than did the tumors in the solvent control group.qPCR analysis and western blotting demonstrated that the mRNA and protein expressions of HIF-1αand HIF-1βwere down-regulated.The expression of HIF-2αand SART1 was up-regulated in the sorafenib treatment group(P<0.05);meanwhile,the expression of HIF-1αand HIF-1βwas up-regulated,and that of HIF-2αand SART1 was down-regulated in the regorafenib treatment group(P<0.05).Conclusion The expression of hypoxia-associated factor is up-regulated by sorafenib and down-regulated by regorafenib,which may induce the different effects of sorafenib on the expression of HIFs.
文摘Background: Colorectal cancer is one of the most common cancer types, frequently metastasizing into the lungs. Treatment options have been vastly improved over the last years. With the increasing use of targeted therapies, novel and rare adverse effects can be seen. Case Presentation: A 43-year-old woman presented in our oncology department with chest pain and dyspnea. The patient was diagnosed with colorectal cancer seven years earlier and had received chemoradiation, surgery, and multiple chemotherapies before she was started on regorafenib because of progressive pulmonary metastases. Computed tomography scans demonstrated cavitation of former nodular bilateral pulmonary metastases. After drainage and resolution of the right-sided pneumothorax, the patient returned eleven days later with recurrent symptoms caused by left-sided tension pneumothorax. Video-assisted thoracoscopy and bilateral pleurodeses were performed. Persistent air leaks with severe pain and pulmonary infiltrates led to the death of the patient. Conclusions: This case demonstrates the efficacy of oral antiangiogenetic therapy in advanced metastatic colorectal cancer. Nevertheless, it also depicts an important potential side effect by transforming multiple solid lung metastases into cavitations which led to recurrent pneumothoraces. Special attention should be paid to this phenomenon as treatment of these complications can be challenging.
基金supported by the National Natural Science Foundation of China under contract No.82203000the Shandong Provincial Natural Science Foundation under contract No.ZR202111120102the Taishan Scholars Program of Shandong Province(tsqnz20221164).
文摘Background and aims:Hepatocellular carcinoma(HCC)is a prevalent and deadly disease with limited treatment options.Regorafenib,a tyrosine kinase inhibitor,has shown promise in HCC treatment but faces limitations as a monotherapy.Combining regorafenib with PD-1 inhibitor may improve efficacy and survival outcomes for patients.This retrospective analysis was conducted to explore its efficacy and safety,providing reference experience for better application of this combination therapy.Methods:This retrospective single-center study evaluated the efficacy and safety of combining regorafenib with PD-1 blockade for patients with HCC.Efficacy was evaluated according to the RECIST 1.1 evaluation criteria.Safety was assessed using CTCAE 4.0.Data was analyzed to compare survival status in different subgroups.Results:Generally,there were 76 patients with HCC elected to receive the regorafenib plus PD-1 blockade treatment during the study period.The objective response rate was 21.1%(n?16),and the disease control rate was 56.6%(n?43).Median progression-free survival(PFS)was 6.8 months,and median overall survival had not yet been reached.All patients suffered of at least 1 adverse event.Grade3 adverse events occurred in 31.6%of patients(n?24),with the most common being hand-foot syndrome,decreased appetite,and abdominal distension.Subgroup analyses showed no significant differences in PFS based on cirrhosis status or previous treatment lines.Conclusion:With manageable safety,regorafenib combined PD-1 inhibitor could bring survival benefits for advanced HCC who have received systemic treatment.Further,the Cox analysis showed that HBV infection,metastasis,etc.did not have significant effects on the survival benefits.
文摘BACKGROUND Gastrointestinal stromal tumors(GISTs)are caused by mutations in the KIT and platelet derived growth factor receptor alpha genes in approximately 90%of cases.A minority of wild-type GISTs are associated with neurofibromatosis type 1(NF1),an autosomal dominant genetic disease resulting from pathogenic mutations in the NF1 gene,which encodes the neurofibromin protein.NF1 patients often exhibit multi-system involvement,with café-au-lait macules and neurofibromas being characteristic symptoms.GISTs are a rare complication of NF1,with the tumors most frequently occurring in the small intestine(90%of cases),while occurrences in the stomach are rare.CASE SUMMARY A 51-year-old woman presented to the emergency department with complaints of dizziness,fatigue,chest tightness,and dark stools.Initial examination revealed a red blood cell count of 1.99×1012/L and a hemoglobin level of 43 g/L.She underwent blood transfusions and fluid replacement to stabilize her condition.Further investigations identified typical café-au-lait macules on her trunk,limbs,and face,along with neurofibromas.Endoscopy showed coffee-colored fluid in the gastric cavity,a large submucosal elevation with an exudative covering,and ulcer formation on the gastric fundus.Exploratory laparoscopy confirmed the tumor’s origin in the gastric fundus,and resection of the giant GIST was performed.Pathological analysis revealed a necrotic GIST measuring 18 cm×14 cm,classified as high-risk,with approximately 5 mitotic figures per 10 high-power fields and no tumor at the margins.Immunohistochemistry results were CD117(+),delay of germination 1(+),CD34(+),and succinate dehydrogenase complex iron sulfur subunit B intact expression.Genetic testing using next-generation sequencing confirmed an NF1 gene mutation.The patient underwent successful tumor resection and was discharged home with postoperative regorafenib therapy.A follow-up at one year showed no recurrence.CONCLUSION Given the diversity of clinical symptoms associated with NF1 and the complexity of NF1-related GISTs,surgical resection with complete tumor removal remains the preferred treatment option.However,the absence of a standardized treatment protocol for adjuvant therapy presents numerous challenges for clinicians.
