Cancer immunotherapy is administered for first-line,second-line,neoadjuvant,or adjuvant treatment of advanced,metastatic,and recurrent cancer in the liver,gastrointestinal tract,and genitourinary tract,and other solid...Cancer immunotherapy is administered for first-line,second-line,neoadjuvant,or adjuvant treatment of advanced,metastatic,and recurrent cancer in the liver,gastrointestinal tract,and genitourinary tract,and other solid tumors.Erdafitinib is a fibroblast growth factor receptor(FGFR)inhibitor,and it is an adenosine triphosphate competitive inhibitor of FGFR1,FGFR2,FGFR3,and FGFR4.Immune checkpoint inhibitors are monoclonal antibodies that block programmed cell death protein 1(PD-1)and its ligand that exert intrinsic antitumor mechanisms.The promising results of first-line treatment of advanced and metastatic urothelial carcinoma with PD-1 blockades with single or combined agents,indicate a new concept in the treatment of advanced,metastatic,and recurrent hepatic and gastrointestinal carcinomas.Cancer immunotherapy as first-line treatment will improve overall survival and provide better quality of life.Debate is arising as to whether to apply the cancer immunotherapy as first-line treatment in invasive carcinomas,or as second-line treatment in recurrent or metastatic carcinoma following the standard chemotherapy.The literature in the field is not definite,and so far,there has been no consensus on the best approach in this situation.At present,as it is described in this editorial,the decision is applied on a case-by-case basis.展开更多
BACKGROUND Liver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality.The pathogenesis of liver cancer is closely associated with inflammation and immu...BACKGROUND Liver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality.The pathogenesis of liver cancer is closely associated with inflammation and immune response in the tumor microenvironment.New therapeutic agents for liver cancer,which can control inflammation and restore cellular immunity,are required.Curcumin(Cur)is a natural anti-inflammatory drug,and total ginsenosides(TG)are a commonly used immunoregulatory drug.Of note,both Cur and TG have been shown to exert anti-liver cancer effects.AIM To determine the synergistic immunomodulatory and anti-inflammatory effects of Cur combined with TG in a mouse model of subcutaneous liver cancer.METHODS A subcutaneous liver cancer model was established in BALB/c mice by a subcutaneous injection of hepatoma cell line.Animals were treated with Cur(200 mg/kg per day),TG(104 mg/kg per day or 520 mg/kg per day),the combination of Cur(200 mg/kg per day)and TG(104 mg/kg per day or 520 mg/kg per day),or 5-fluorouracil combined with cisplatin as a positive control for 21 d.Tumor volume was measured and the protein expression of programmed cell death 1 and programmed cell death 1 ligand 1(PD-L1),inflammatory indicators Toll like receptor 4(TLR4)and nuclear factor-κB(NF-κB),and vascular growth-related factors nitric oxide synthases(iNOS)and matrix metalloproteinase 9 were analyzed by Western blot analysis.CD4+CD25+Foxp3+regulatory T cells(Tregs)were counted by flow cytometry.RESULTS The combination therapy of Cur and TG significantly inhibited the growth of liver cancer,as compared to vehicle-treated animals,and TG showed dose dependence.Cur combined with TG-520 markedly decreased the protein expression of PD-L1(P<0.0001),while CD4+CD25+Foxp3+Tregs regulated by the PD-L1 signaling pathway exhibited a positive correlation with PD-L1.Cur combined with TG-520 also inhibited the cascade action mediated by NF-κB(P<0.0001),thus inhibiting the TLR4/NF-κB signalling pathway(P=0.0088,P<0.0001),which is associated with inflammation and acts on PD-L1.It also inhibited the NF-κB-MMP9 signalling pathway(P<0.0001),which is associated with tumor angiogenesis.CONCLUSION Cur combined with TG regulates immune escape through the PD-L1 pathway and inhibits liver cancer growth through NF-κB-mediated inflammation and angiogenesis.展开更多
BACKGROUND Both programmed cell death-1(PD-1)inhibitors and lenvatinib,which have a synergistic effect,are promising drugs for tumor treatment.It is generally believed that combination therapy with a PD-1 inhibitor an...BACKGROUND Both programmed cell death-1(PD-1)inhibitors and lenvatinib,which have a synergistic effect,are promising drugs for tumor treatment.It is generally believed that combination therapy with a PD-1 inhibitor and lenvatinib is safe and effective.However,we report a case of toxic epidermal necrolysis(TEN),a grade 4 toxicity,after this combination therapy.CASE SUMMARY A 39-year-old male presented with erythema,blisters and erosions on the face,neck,trunk and limbs 1 wk after receiving combination therapy with lenvatinib and toripalimab,a PD-1 inhibitor.The skin injury covered more than 70%of the body surface area.He was previously diagnosed with liver cancer with cervical vertebra metastasis.Histologically,prominent necrotic keratinocytes,hyperkeratosis,liquefaction of basal cells and acantholytic bullae were observed in the epidermis.Blood vessels in the dermis were infiltrated by lymphocytes and eosinophils.Direct immunofluorescence staining was negative.Thus,the diagnosis was confirmed to be TEN(associated with combination therapy with toripalimab and lenvatinib).Full-dose and long-term corticosteroids,high-dose intravenous immunoglobulin and targeted antibiotic drugs were administered.The rashes gradually faded;however,as expected,the tumor progressed.Therefore, sorafenib and regorafenib were given in succession, and the patient was still alive at the10-mo follow-up.CONCLUSIONCautious attention should be given to rashes that develop after combination therapy with PD-1inhibitors and lenvatinib. Large-dose and long-course glucocorticoids may be crucial for thetreatment of TEN associated with this combination treatment.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)represents the most common primitive liver malignancy.A relevant concern involves the lack of agreement on staging systems,prognostic scores,and treatment allocation algorithms....BACKGROUND Hepatocellular carcinoma(HCC)represents the most common primitive liver malignancy.A relevant concern involves the lack of agreement on staging systems,prognostic scores,and treatment allocation algorithms.AIM To compare the survival rates among already developed prognostic scores.METHODS We retrospectively evaluated 140 patients with HCC diagnosed between February 2006 and November 2017.Patients were categorized according to 15 prognostic scoring systems and estimated median survivals were compared with those available from the current medical literature.RESULTS The median overall survival of the cohort of patients was 35(17;67)mo,and it was statistically different in relation to treatment choice,ultrasound surveillance,and serum alpha-fetoprotein.The Italian Liver Cancer(ITA.LI.CA)tumor staging system performed best in predicting survival according to stage allocation among all 15 evaluated prognostic scores.Using the ITA.LI.CA prognostic system,28.6%,40.7%,22.1%,and 8.6%of patients fell within stages 0-1,2-3,4-5 and>5 respectively.The median survival was 57.9 mo for stages 0-1,43 mo for stages 2-3,21.7 mo for stages 4-5,and 10.4 mo for stage>5.The 1-,3-,and 5-year survival rates were respectively 95%,65%,and 20%,for stages 0-1;94.7%,43.9%and 26.3%for stages 2-3;71%,25.8%and 16.1%for stages 4-5;and 50%,16.7%and 8.3%for stage>5.At the same time,although statistically significant in prognostic stratification,the most commonly used Barcelona Clinic Liver Cancer system showed one of the most relevant differences in median survival,especially for stages A and C,when compared to the medical literature.In fact,10.7%,59.3%,27.1%,1.4%,and 0%of patients were stratified into stages 0,A,B,C,and D respectively.The median survival was>81.1 mo for stage 0,44.9 mo for stage A,21.3 mo for stage B,and 3.1 mo for stage C.The 1-,3-,and 5-year survival rates were respectively 86.7%,60%,and 46.7%for stage 0;91.6%,50.6%,and 20.5%for stage A;73.7%,23.7%and 13.2%for stage B;and 2%,0%and 0%for stage C.CONCLUSION Survival analysis shows excellent prognostic ability of the ITA.LI.CA scoring system compared to other staging systems.展开更多
AIM: To investigate risk factors for hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT) and efficacy of various criteria. METHODS: From October 2000 to November 2011, 233 adult p...AIM: To investigate risk factors for hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT) and efficacy of various criteria. METHODS: From October 2000 to November 2011, 233 adult patients underwent LDLT for HCC at our institution. After excluding nine postoperative mortality cases, we analyzed retrospectively 224 patients. To identify risk factors for recurrence, we evaluated recurrence, disease-free survival (DFS) rate, survival rate, and various other factors which are based on the characteristics of both the patient and tumor. Additionally, we developed our own criteria based on our data. Next, we compared our selection criteria with various tumor-grading scales, such as the Milan criteria, University of California, San Francisco (UCSF) criteria, TNM stage, Barcelona Clinic Liver Cancer (BCLC) stage and Cancer of the Liver Italian Program (CLIP) scoring system. The median follow up was 68 (6-139) mo.RESULTS: In 224 patients who received LDLT for HCC, 37 (16.5%) experienced tumor recurrence during the follow-up period. The 5-year DFS and overall survival rates after LDLT in all patients with HCC were 80.9% and 76.4%, respectively. On multivariate analysis, the tumor diameter {5 cm; P < 0.001; exponentiation of the B coefficient [Exp(B)], 11.89; 95%CI: 3.784-37.368} and alpha fetoprotein level [AFP, 100 ng/mL; P = 0.021; Exp(B), 2.892; 95%CI: 1.172-7.132] had significant influences on HCC recurrence after LDLT. Therefore, these two factors were included in our criteria. Based on these data, we set our selection criteria as a tumor diameter ≤ 5 cm and AFP ≤ 100 ng/mL. Within our new criteria (140/214, 65.4%), the 5-year DFS and overall survival rates were 88.6% and 81.8%, respectively. Our criteria (P = 0.001), Milan criteria (P = 0.009), and UCSF criteria (P = 0.001) showed a significant difference in DFS rate. And our criteria (P = 0.006) and UCSF criteria (P = 0.009) showed a significant difference in overall survival rate. But Milan criteria did not show significant difference in overall survival rate (P = 0.137). Among stages 0, A, B and C of BCLC, stage C had a significantly higher recurrence rate (P = 0.001), lower DFS (P = 0.001), and overall survival rate (P = 0.005) compared with the other stages. Using the CLIP scoring system, the group with a score of 4 to 5 showed a high recurrence rate (P = 0.023) and lower DFS (P = 0.011); however, the overall survival rate did not differ from that of the lower scoring group. The TNM system showed a trend of increased recurrence rate, decreased DFS, or survival rate according to T stage, albeit without statistical significance. CONCLUSION: LDLT is considered the preferred therapeutic option in patients with an AFP level less than 100 ng/mL and a tumor diameter of less than 5 cm.展开更多
Immune checkpoint inhibitors(ICIs)like programmed cell death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor have shown considerable efficacy in several important cancers including primary liver cancer(PLC)like hepa...Immune checkpoint inhibitors(ICIs)like programmed cell death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor have shown considerable efficacy in several important cancers including primary liver cancer(PLC)like hepatocellular carcinoma and cholangiocarcinoma.However,only some patients with PLC will benefit,so combination therapy and biomarker classification detected by next-generation sequencing or immunohistochemistry are very important.Herein,we briefly summarize ICI-based therapies and stratify these evolving therapies for advanced PLC into three stages of immunotherapies Mark(Mk.)1.0,2.0,and 3.0.We illustrated the significance of ICI monotherapy(Mk.1.0),offering combinational approaches with traditional strategies(Mk.2.0)and additional locoregional therapy(Mk.3.0)to achieve longer survival and even meet the“No Evidence of Disease”status.We also highlight the importance of biomarkers and prognostic factors for patients with advanced PLC treated with ICI-based therapies.Multidisci-plinary team management should be investigated and collaborated closely to manage adverse events and sequential therapy suggestions for patients.展开更多
文摘Cancer immunotherapy is administered for first-line,second-line,neoadjuvant,or adjuvant treatment of advanced,metastatic,and recurrent cancer in the liver,gastrointestinal tract,and genitourinary tract,and other solid tumors.Erdafitinib is a fibroblast growth factor receptor(FGFR)inhibitor,and it is an adenosine triphosphate competitive inhibitor of FGFR1,FGFR2,FGFR3,and FGFR4.Immune checkpoint inhibitors are monoclonal antibodies that block programmed cell death protein 1(PD-1)and its ligand that exert intrinsic antitumor mechanisms.The promising results of first-line treatment of advanced and metastatic urothelial carcinoma with PD-1 blockades with single or combined agents,indicate a new concept in the treatment of advanced,metastatic,and recurrent hepatic and gastrointestinal carcinomas.Cancer immunotherapy as first-line treatment will improve overall survival and provide better quality of life.Debate is arising as to whether to apply the cancer immunotherapy as first-line treatment in invasive carcinomas,or as second-line treatment in recurrent or metastatic carcinoma following the standard chemotherapy.The literature in the field is not definite,and so far,there has been no consensus on the best approach in this situation.At present,as it is described in this editorial,the decision is applied on a case-by-case basis.
基金the National Natural Science Foundation of China,No.81473617the Science and Technology Department of Hunan Province,No.2017SK50310the Hunan Education Department’s Science and Research Project,No.16K066.
文摘BACKGROUND Liver cancer is the sixth most frequently occurring cancer in the world and the fourth most common cause of cancer mortality.The pathogenesis of liver cancer is closely associated with inflammation and immune response in the tumor microenvironment.New therapeutic agents for liver cancer,which can control inflammation and restore cellular immunity,are required.Curcumin(Cur)is a natural anti-inflammatory drug,and total ginsenosides(TG)are a commonly used immunoregulatory drug.Of note,both Cur and TG have been shown to exert anti-liver cancer effects.AIM To determine the synergistic immunomodulatory and anti-inflammatory effects of Cur combined with TG in a mouse model of subcutaneous liver cancer.METHODS A subcutaneous liver cancer model was established in BALB/c mice by a subcutaneous injection of hepatoma cell line.Animals were treated with Cur(200 mg/kg per day),TG(104 mg/kg per day or 520 mg/kg per day),the combination of Cur(200 mg/kg per day)and TG(104 mg/kg per day or 520 mg/kg per day),or 5-fluorouracil combined with cisplatin as a positive control for 21 d.Tumor volume was measured and the protein expression of programmed cell death 1 and programmed cell death 1 ligand 1(PD-L1),inflammatory indicators Toll like receptor 4(TLR4)and nuclear factor-κB(NF-κB),and vascular growth-related factors nitric oxide synthases(iNOS)and matrix metalloproteinase 9 were analyzed by Western blot analysis.CD4+CD25+Foxp3+regulatory T cells(Tregs)were counted by flow cytometry.RESULTS The combination therapy of Cur and TG significantly inhibited the growth of liver cancer,as compared to vehicle-treated animals,and TG showed dose dependence.Cur combined with TG-520 markedly decreased the protein expression of PD-L1(P<0.0001),while CD4+CD25+Foxp3+Tregs regulated by the PD-L1 signaling pathway exhibited a positive correlation with PD-L1.Cur combined with TG-520 also inhibited the cascade action mediated by NF-κB(P<0.0001),thus inhibiting the TLR4/NF-κB signalling pathway(P=0.0088,P<0.0001),which is associated with inflammation and acts on PD-L1.It also inhibited the NF-κB-MMP9 signalling pathway(P<0.0001),which is associated with tumor angiogenesis.CONCLUSION Cur combined with TG regulates immune escape through the PD-L1 pathway and inhibits liver cancer growth through NF-κB-mediated inflammation and angiogenesis.
基金Supported by Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases,No. 2018B030322012
文摘BACKGROUND Both programmed cell death-1(PD-1)inhibitors and lenvatinib,which have a synergistic effect,are promising drugs for tumor treatment.It is generally believed that combination therapy with a PD-1 inhibitor and lenvatinib is safe and effective.However,we report a case of toxic epidermal necrolysis(TEN),a grade 4 toxicity,after this combination therapy.CASE SUMMARY A 39-year-old male presented with erythema,blisters and erosions on the face,neck,trunk and limbs 1 wk after receiving combination therapy with lenvatinib and toripalimab,a PD-1 inhibitor.The skin injury covered more than 70%of the body surface area.He was previously diagnosed with liver cancer with cervical vertebra metastasis.Histologically,prominent necrotic keratinocytes,hyperkeratosis,liquefaction of basal cells and acantholytic bullae were observed in the epidermis.Blood vessels in the dermis were infiltrated by lymphocytes and eosinophils.Direct immunofluorescence staining was negative.Thus,the diagnosis was confirmed to be TEN(associated with combination therapy with toripalimab and lenvatinib).Full-dose and long-term corticosteroids,high-dose intravenous immunoglobulin and targeted antibiotic drugs were administered.The rashes gradually faded;however,as expected,the tumor progressed.Therefore, sorafenib and regorafenib were given in succession, and the patient was still alive at the10-mo follow-up.CONCLUSIONCautious attention should be given to rashes that develop after combination therapy with PD-1inhibitors and lenvatinib. Large-dose and long-course glucocorticoids may be crucial for thetreatment of TEN associated with this combination treatment.
文摘BACKGROUND Hepatocellular carcinoma(HCC)represents the most common primitive liver malignancy.A relevant concern involves the lack of agreement on staging systems,prognostic scores,and treatment allocation algorithms.AIM To compare the survival rates among already developed prognostic scores.METHODS We retrospectively evaluated 140 patients with HCC diagnosed between February 2006 and November 2017.Patients were categorized according to 15 prognostic scoring systems and estimated median survivals were compared with those available from the current medical literature.RESULTS The median overall survival of the cohort of patients was 35(17;67)mo,and it was statistically different in relation to treatment choice,ultrasound surveillance,and serum alpha-fetoprotein.The Italian Liver Cancer(ITA.LI.CA)tumor staging system performed best in predicting survival according to stage allocation among all 15 evaluated prognostic scores.Using the ITA.LI.CA prognostic system,28.6%,40.7%,22.1%,and 8.6%of patients fell within stages 0-1,2-3,4-5 and>5 respectively.The median survival was 57.9 mo for stages 0-1,43 mo for stages 2-3,21.7 mo for stages 4-5,and 10.4 mo for stage>5.The 1-,3-,and 5-year survival rates were respectively 95%,65%,and 20%,for stages 0-1;94.7%,43.9%and 26.3%for stages 2-3;71%,25.8%and 16.1%for stages 4-5;and 50%,16.7%and 8.3%for stage>5.At the same time,although statistically significant in prognostic stratification,the most commonly used Barcelona Clinic Liver Cancer system showed one of the most relevant differences in median survival,especially for stages A and C,when compared to the medical literature.In fact,10.7%,59.3%,27.1%,1.4%,and 0%of patients were stratified into stages 0,A,B,C,and D respectively.The median survival was>81.1 mo for stage 0,44.9 mo for stage A,21.3 mo for stage B,and 3.1 mo for stage C.The 1-,3-,and 5-year survival rates were respectively 86.7%,60%,and 46.7%for stage 0;91.6%,50.6%,and 20.5%for stage A;73.7%,23.7%and 13.2%for stage B;and 2%,0%and 0%for stage C.CONCLUSION Survival analysis shows excellent prognostic ability of the ITA.LI.CA scoring system compared to other staging systems.
文摘AIM: To investigate risk factors for hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT) and efficacy of various criteria. METHODS: From October 2000 to November 2011, 233 adult patients underwent LDLT for HCC at our institution. After excluding nine postoperative mortality cases, we analyzed retrospectively 224 patients. To identify risk factors for recurrence, we evaluated recurrence, disease-free survival (DFS) rate, survival rate, and various other factors which are based on the characteristics of both the patient and tumor. Additionally, we developed our own criteria based on our data. Next, we compared our selection criteria with various tumor-grading scales, such as the Milan criteria, University of California, San Francisco (UCSF) criteria, TNM stage, Barcelona Clinic Liver Cancer (BCLC) stage and Cancer of the Liver Italian Program (CLIP) scoring system. The median follow up was 68 (6-139) mo.RESULTS: In 224 patients who received LDLT for HCC, 37 (16.5%) experienced tumor recurrence during the follow-up period. The 5-year DFS and overall survival rates after LDLT in all patients with HCC were 80.9% and 76.4%, respectively. On multivariate analysis, the tumor diameter {5 cm; P < 0.001; exponentiation of the B coefficient [Exp(B)], 11.89; 95%CI: 3.784-37.368} and alpha fetoprotein level [AFP, 100 ng/mL; P = 0.021; Exp(B), 2.892; 95%CI: 1.172-7.132] had significant influences on HCC recurrence after LDLT. Therefore, these two factors were included in our criteria. Based on these data, we set our selection criteria as a tumor diameter ≤ 5 cm and AFP ≤ 100 ng/mL. Within our new criteria (140/214, 65.4%), the 5-year DFS and overall survival rates were 88.6% and 81.8%, respectively. Our criteria (P = 0.001), Milan criteria (P = 0.009), and UCSF criteria (P = 0.001) showed a significant difference in DFS rate. And our criteria (P = 0.006) and UCSF criteria (P = 0.009) showed a significant difference in overall survival rate. But Milan criteria did not show significant difference in overall survival rate (P = 0.137). Among stages 0, A, B and C of BCLC, stage C had a significantly higher recurrence rate (P = 0.001), lower DFS (P = 0.001), and overall survival rate (P = 0.005) compared with the other stages. Using the CLIP scoring system, the group with a score of 4 to 5 showed a high recurrence rate (P = 0.023) and lower DFS (P = 0.011); however, the overall survival rate did not differ from that of the lower scoring group. The TNM system showed a trend of increased recurrence rate, decreased DFS, or survival rate according to T stage, albeit without statistical significance. CONCLUSION: LDLT is considered the preferred therapeutic option in patients with an AFP level less than 100 ng/mL and a tumor diameter of less than 5 cm.
基金supported by National High Level Hospital Clinical Research Funding[2022-PUMCH-B-128],CAMS Innovation Fund for Medical Sciences(CIFMS)[2022-I2M-C&T-A-003][2021-I2M-1-061][2021-I2M-1-003]CSCO-hengrui Cancer Research Fund[Y-HR2019-0239][Y-HR2020MS-0415][Y-HR2020QN-0414]CSCO-MSD Cancer Research Fund[Y-MSDZD2021-0213]and National Ten-Thousand Talent Program.
文摘Immune checkpoint inhibitors(ICIs)like programmed cell death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor have shown considerable efficacy in several important cancers including primary liver cancer(PLC)like hepatocellular carcinoma and cholangiocarcinoma.However,only some patients with PLC will benefit,so combination therapy and biomarker classification detected by next-generation sequencing or immunohistochemistry are very important.Herein,we briefly summarize ICI-based therapies and stratify these evolving therapies for advanced PLC into three stages of immunotherapies Mark(Mk.)1.0,2.0,and 3.0.We illustrated the significance of ICI monotherapy(Mk.1.0),offering combinational approaches with traditional strategies(Mk.2.0)and additional locoregional therapy(Mk.3.0)to achieve longer survival and even meet the“No Evidence of Disease”status.We also highlight the importance of biomarkers and prognostic factors for patients with advanced PLC treated with ICI-based therapies.Multidisci-plinary team management should be investigated and collaborated closely to manage adverse events and sequential therapy suggestions for patients.
