AIM:To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer.METHODS:A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study....AIM:To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer.METHODS:A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study.Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer.Patients were divided into study (infection) group and control (non-infection) group.Clinical features of patients in two groups were compared.RESULTS:Liver metastasis was found in 319 out of the 1298 colorectal cancer patients.The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%,P < 0.01).HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR):0.50,95% confidence interval (95% CI):0.38-0.66],but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%,P < 0.01).The HR was the lowest in chronic hepatitis B group (HR:0.29,95% CI:0.12-0.72).The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate.However,no significant difference was found in survival rate between the two groups (P=0.95).CONCLUSION:HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions.展开更多
AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer.
Colorectal cancer(CRC)is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide.The treatment of advanced CRC has improved significantly in recent years.With th...Colorectal cancer(CRC)is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide.The treatment of advanced CRC has improved significantly in recent years.With the emergence of two targeted antibodies,cetuximab(Erbitux),an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab(Avastin),a vascular endothelial growth factor monoclonal antibody,the treatment of metastatic CRC has entered the era of personalized therapy.Predictive and prognostic biomarkers have,and will continue to,facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC(mCRC).In this review,we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.展开更多
Background:Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer.This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1,oxaliplatin,and leucovori...Background:Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer.This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1,oxaliplatin,and leucovorin(SOL) in the treatment of Chinese patients with metastatic colorectal cancer(mCRC).Methods:Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin(85 mg/m2) on day 1,oral S-1 twice daily(80-120 mg per day) on day 1-7,and leucovorin twice daily(50 mg per day)simultaneously with S-1,every 2 weeks.Results and discussion:Forty patients were enrolled in our study.In total,296 cycles of SOL were administered.The overall response rate was 50.0%.At a median follow-up of 27 months,progression-free survival and overall surviva were 7.0 months(95%confidence interval[CI]6.0-10.6 months) and 22.2 months(95%CI 15.1-29.3 months),respectively.The most common grade 3/4 non-hematological adverse events were diarrhea(n = 8,20.0%),nausea(n = 3,7.5%),and vomiting(n = 3,7.5%).The most common grade 3/4 hematological toxicities were thrombocytopenia(n = 3,7.5%),neutropenia(n = 1,2.5%),and abnormal alanine transaminase/aspartate transaminase levels(n = 1,2.5%).There was one treatment-related death.Conclusions:The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.Trial registration:Clinical trial展开更多
AIM: To investigate adjuvant chemotherapy, p53 and carcinoembryonic antigen (CEA) expression and prognosis after D2 gastrectomy for stage II/III gastric adenocarcinoma.
BACKGROUND The number of elderly individuals with diabetes is dramatically increasing.Diabetes is a long-term condition and a noncommunicable disease and requires intensive daily self-management.Understanding of self-...BACKGROUND The number of elderly individuals with diabetes is dramatically increasing.Diabetes is a long-term condition and a noncommunicable disease and requires intensive daily self-management.Understanding of self-management from the patients’perspectives is important to nurses,healthcare providers,and researchers and benefits people by improving their self-management skills.AIM To examine and synthesize qualitative studies that explore the experiences of elderly people in self-managing diabetes.METHODS Electronic databases were searched,including MEDLINE,CINAH,PsycINFO,PubMed,CNKI,and WANFADATA.Relevant research was identified by manually searching reference lists and gray literature.Only English and Chinese publications were included.The Critical Appraisal Skills Program was used to assess the quality of the research.The Confidence in the Evidence from Reviews of Qualitative research approach was used to assess the confidence of the findings.RESULTS A total of 10 qualitative studies were included,and content analysis was performed.Five themes were identified:The need for knowledge about diabetes care,support systems,functional decline,attitudes toward diabetes,and healthy lifestyle challenges.CONCLUSION This present review provides a deep and broad understanding of the experiences in the self-management of diabetes and can be valuable to nursing practice and provide recommendations for future research.展开更多
There is a lack of high-quality,large-scale,real-world evidence from patients with metastatic colorectal cancer(mCRC),especially in China.It remains unclear whether efforts to improve the quality of care for mCRC woul...There is a lack of high-quality,large-scale,real-world evidence from patients with metastatic colorectal cancer(mCRC),especially in China.It remains unclear whether efforts to improve the quality of care for mCRC would improve patient survival outcomes in real-world practice.On the basis of an intelligent bigdata platform,we established a large-scale retrospective cohort of mCRC patients.We investigated the temporal changes in the systemic and local treatment(resection,ablation,or radiation to liver,lung,or extrahepatic and/or extrapulmonary metastases)patterns of mCRC,and whether these changes were associated with improved overall survival(OS)over time.Between July 2012 and December 2018,3403 eligible patients were included in this research.The median OS was 42.8 months(95%confidence interval(CI),40.7–46.6)for the entire cohort,25.6 months(95%CI,24.7–26.9)for those treated with systemic therapy only,and not reached(95%CI,78.6 months–not reached)for those receiving local therapy.The utility rate of local therapy increased continuously from 37.9%in 2012–2014 to 46.9%in 2017–2018.A dramatic increase in the utility rate of either cetuximab or bevacizumab was observed since 2017(39.9%,43.2%,and 60.3%in 2012–2014,2015–2016,and 2017–2018,respectively).Compared with 2012–2014,the OS of the entire population significantly improved in 2015–2016(hazard ratio(HR)=0.87(95%CI,0.78–0.99);P=0.034),but not for patients receiving systemic therapy only(HR=0.99(95%CI,0.86–1.14);P=0.889),whereas an improved OS was found in 2015–2018 for both the entire population(HR=0.75(95%CI,0.70–0.81);P<0.001)and for patients receiving systemic therapy only(HR=0.83(95%CI,0.77–0.91);P<0.001).In summary,the quality of care for mCRC,as indicated by the utility rate of targeted and local therapies,has been continuously improving over time in this study cohort,which is associated with continuously improving survival outcomes for these patients.展开更多
Epstein-Barr virus(EBV)-associated gastric cancer(GC)manifests an intriguing immunotherapy response.However,the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined.This study a...Epstein-Barr virus(EBV)-associated gastric cancer(GC)manifests an intriguing immunotherapy response.However,the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined.This study aimed to finely characterize the dynamic tumour immune contexture of human EBV(+)GC treated with immunochemotherapy by longitudinal scRNA-seg and paired scTCR/BCR-seq.EBV(+)GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration.展开更多
Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have ...Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.展开更多
1 BACKGROUND With the rapid development of immune checkpoint inhibitors(ICIs)over the past decades,they have become a major area of interest in the treatment of colorectal cancer(CRC)[1,2].There are evidence pointing ...1 BACKGROUND With the rapid development of immune checkpoint inhibitors(ICIs)over the past decades,they have become a major area of interest in the treatment of colorectal cancer(CRC)[1,2].There are evidence pointing that programmed cell death protein-1(PD-1)blockade,alone or in combination with anti-cytotoxic T-lymphocyte-associated protein 4(anti-CTLA4)therapy,achieved durable responses in patients with mismatch repair-deficient(dMMR)or microsatellite instability-high(MSI-H)metastatic CRC(mCRC)[3–6].However,the optimal diagnostic method for detecting dMMR/MSI-H disease as well as the optimal anti-PD-1-based treatment modality still remains controversial in this patient subset.In addition,for the majority of mCRC cases that are mismatch repair-proficient(pMMR)or microsatellite stable(MSS),the clinical benefits from these agents are generally minimal[3,7],driving extensive research efforts to develop effective combination therapies in this disease subset.Moreover,investigations of anti-PD-1-based treatments have also been initiated in the nonmetastatic settings of CRC,with some encouraging preliminary evidence[8].Medical oncologists and surgeons from the Committee of Colorectal Cancer of the Chinese Society of Clinical Oncology had a panel discussion on immunotherapy for patients with colorectal cancer during a seminar on June 16,2020,in Guangzhou,China.Herein,the expert opinions have been summarized along with relevant clinical evidence(Table 1)to guide real-world treatment decision-making regarding the use of ICIs in patients with CRC.展开更多
Background: Oxaliplatin, irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRINOX) has become one of the first-line treatment options for advanced pancreatic cancer (PC). However, the relatively high rate of grade 3 o...Background: Oxaliplatin, irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRINOX) has become one of the first-line treatment options for advanced pancreatic cancer (PC). However, the relatively high rate of grade 3 or 4 adverse events associated with the standard dosage of FOLFIRINOX limits its widespread use in clinical practice. In this study, we were to evaluate the efficacy and safety of a modified FOLFIRINOX regimen as a first-line chemotherapy for Chinese patients with metastatic PC. Methods: Patients with histologically confirmed primary metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 were recruited to receive the modified FOLFIRINOX regimen (intravenous infusion of oxaliplatin, 65 mg/m2;irinotecan, 150 mg/m2;l-leucovorin, 200 mg/ m2;and 5-fluorouracil, 2400 mg/m2, repeated every 2 weeks). The treatment was continued for 12 cycles unless the patient had progressive disease (PD), stable disease (SD) with symptom deterioration, unacceptable adverse events, or requested to terminate the treatment prematurely. The primary endpoint was objective response rate (ORR). Results: Sixty-five patients were enrolled from July 2012 to April 2017 in three institutions, and they all received at least one cycle of chemotherapy, with a median of 8 cycles (range 1-12 cycles). No complete response was observed. Twenty-one (32.3%) patients had partial responses, and 27 (41.5%) had SD. The ORR and disease control rate of the study cohort was 32.3% and 73.8%. The estimated median overall survival and progression-free survival were 11.60 (95% confidence interval [CI] 8.76-14.44) and 5.77 (95% CI 5.00-6.54) months. Major grade 3 or 4 adverse events included neutropenia (12.3%) and diarrhea (6.2%). No treatment-related death was observed. Conclusions: Modified FOLFIRINOX was well-tolerated and might be a promising option as first-line therapy for Chinese patients with metastatic PC.展开更多
The acidic tumor microenvironment provides an energy source driving malignant tumor progression.Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells.The expression of the vitamin D ...The acidic tumor microenvironment provides an energy source driving malignant tumor progression.Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells.The expression of the vitamin D receptor(VDR)is closely related to the initiation and development of colorectal carcinoma(CRC),but its regulatory mechanism in CRC stem cells is still unclear.Our study revealed that acidosis reduced VDR expression by downregulating peroxisome proliferator-activated receptor delta(PPARD)expression.Overexpression of VDR effectively suppressed the stemness and oxaliplatin resistance of cells in acidosis.The nuclear export signal in VDR was sensitive to acidosis,and VDR was exported from the nucleus.Chromatin immunoprecipitation(ChIP)and assay for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq)analyses showed that VDR transcriptionally repressed SRY-box 2(SOX2)by binding to the vitamin D response elements in the promoter of SOX2,impairing tumor growth and drug resistance.We demonstrated that a change in the acidic microenvironment combined with overexpression of VDR substantially restricted the occurrence and development of CRC in vivo.These findings reveal a new mechanism by which acidosis could affect the stemness of CRC cells by regulating the expression of SOX2 and show that abnormal VDR expression leads to ineffective activation of vitamin D signaling,resulting in a lack of efficacy of vitamin D in antineoplastic process.展开更多
基金Supported by National Natural Science Foundation of China,No.30672408
文摘AIM:To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer.METHODS:A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study.Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer.Patients were divided into study (infection) group and control (non-infection) group.Clinical features of patients in two groups were compared.RESULTS:Liver metastasis was found in 319 out of the 1298 colorectal cancer patients.The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%,P < 0.01).HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR):0.50,95% confidence interval (95% CI):0.38-0.66],but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%,P < 0.01).The HR was the lowest in chronic hepatitis B group (HR:0.29,95% CI:0.12-0.72).The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate.However,no significant difference was found in survival rate between the two groups (P=0.95).CONCLUSION:HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions.
基金Supported by National High Technology Research and Development Program of China(863 Program),No.2012AA02A506National Natural Science Foundation of China,No.81372570+1 种基金the Science and Technology Foundation of Guangdong Province,China,No.2012B031800088the Science and Technology Foundation of Guangdong Province,China,No.C2011019
文摘AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer.
基金Supported by National High-Tech R and D Program of China,863 Program,No.2012AA02A506The Science and Technology Department of Guangdong Province,China,No.2012B031800088
文摘Colorectal cancer(CRC)is one of the most common human malignant diseases and the second leading cause of cancer-related deaths worldwide.The treatment of advanced CRC has improved significantly in recent years.With the emergence of two targeted antibodies,cetuximab(Erbitux),an anti-epidermal growth factor receptor monoclonal antibody and bevacizumab(Avastin),a vascular endothelial growth factor monoclonal antibody,the treatment of metastatic CRC has entered the era of personalized therapy.Predictive and prognostic biomarkers have,and will continue to,facilitate the selection of suitable patients and the personalization of treatment for metastatic CRC(mCRC).In this review,we will focus primarily on the important progresses made in the personalized treatment of mCRC and discuss the potentially novel predictive and prognostic biomarkers for improved selection of patients for anti-cancer treatment in the future.
文摘Background:Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer.This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1,oxaliplatin,and leucovorin(SOL) in the treatment of Chinese patients with metastatic colorectal cancer(mCRC).Methods:Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin(85 mg/m2) on day 1,oral S-1 twice daily(80-120 mg per day) on day 1-7,and leucovorin twice daily(50 mg per day)simultaneously with S-1,every 2 weeks.Results and discussion:Forty patients were enrolled in our study.In total,296 cycles of SOL were administered.The overall response rate was 50.0%.At a median follow-up of 27 months,progression-free survival and overall surviva were 7.0 months(95%confidence interval[CI]6.0-10.6 months) and 22.2 months(95%CI 15.1-29.3 months),respectively.The most common grade 3/4 non-hematological adverse events were diarrhea(n = 8,20.0%),nausea(n = 3,7.5%),and vomiting(n = 3,7.5%).The most common grade 3/4 hematological toxicities were thrombocytopenia(n = 3,7.5%),neutropenia(n = 1,2.5%),and abnormal alanine transaminase/aspartate transaminase levels(n = 1,2.5%).There was one treatment-related death.Conclusions:The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.Trial registration:Clinical trial
基金Supported by National High Technology Research and Development Program of China(863 Program),China,No.2012AA02A506Science and Technology Department of Guangdong Province,China,No.2012B031800088Medical Scientific Research Foundation of Guangdong Province,China,No.C2011019
文摘AIM: To investigate adjuvant chemotherapy, p53 and carcinoembryonic antigen (CEA) expression and prognosis after D2 gastrectomy for stage II/III gastric adenocarcinoma.
文摘BACKGROUND The number of elderly individuals with diabetes is dramatically increasing.Diabetes is a long-term condition and a noncommunicable disease and requires intensive daily self-management.Understanding of self-management from the patients’perspectives is important to nurses,healthcare providers,and researchers and benefits people by improving their self-management skills.AIM To examine and synthesize qualitative studies that explore the experiences of elderly people in self-managing diabetes.METHODS Electronic databases were searched,including MEDLINE,CINAH,PsycINFO,PubMed,CNKI,and WANFADATA.Relevant research was identified by manually searching reference lists and gray literature.Only English and Chinese publications were included.The Critical Appraisal Skills Program was used to assess the quality of the research.The Confidence in the Evidence from Reviews of Qualitative research approach was used to assess the confidence of the findings.RESULTS A total of 10 qualitative studies were included,and content analysis was performed.Five themes were identified:The need for knowledge about diabetes care,support systems,functional decline,attitudes toward diabetes,and healthy lifestyle challenges.CONCLUSION This present review provides a deep and broad understanding of the experiences in the self-management of diabetes and can be valuable to nursing practice and provide recommendations for future research.
基金This study was supported by the grants from the National Natural Science Foundation of China(81930065)the Natural Science Foundation of Guangdong Province(2014A030312015)+1 种基金the Science and Technology Program of Guangdong(2019B020227002)the Science and Technology Program of Guangzhou(201904020046,201803040019,and 201704020228).
文摘There is a lack of high-quality,large-scale,real-world evidence from patients with metastatic colorectal cancer(mCRC),especially in China.It remains unclear whether efforts to improve the quality of care for mCRC would improve patient survival outcomes in real-world practice.On the basis of an intelligent bigdata platform,we established a large-scale retrospective cohort of mCRC patients.We investigated the temporal changes in the systemic and local treatment(resection,ablation,or radiation to liver,lung,or extrahepatic and/or extrapulmonary metastases)patterns of mCRC,and whether these changes were associated with improved overall survival(OS)over time.Between July 2012 and December 2018,3403 eligible patients were included in this research.The median OS was 42.8 months(95%confidence interval(CI),40.7–46.6)for the entire cohort,25.6 months(95%CI,24.7–26.9)for those treated with systemic therapy only,and not reached(95%CI,78.6 months–not reached)for those receiving local therapy.The utility rate of local therapy increased continuously from 37.9%in 2012–2014 to 46.9%in 2017–2018.A dramatic increase in the utility rate of either cetuximab or bevacizumab was observed since 2017(39.9%,43.2%,and 60.3%in 2012–2014,2015–2016,and 2017–2018,respectively).Compared with 2012–2014,the OS of the entire population significantly improved in 2015–2016(hazard ratio(HR)=0.87(95%CI,0.78–0.99);P=0.034),but not for patients receiving systemic therapy only(HR=0.99(95%CI,0.86–1.14);P=0.889),whereas an improved OS was found in 2015–2018 for both the entire population(HR=0.75(95%CI,0.70–0.81);P<0.001)and for patients receiving systemic therapy only(HR=0.83(95%CI,0.77–0.91);P<0.001).In summary,the quality of care for mCRC,as indicated by the utility rate of targeted and local therapies,has been continuously improving over time in this study cohort,which is associated with continuously improving survival outcomes for these patients.
基金This work was supported by National Natural Science Foundation of China(81930065,82173128 to R-H.X.,82073377,81772587 to M.Z.Q.,82172861 to Q.Z.)CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-12M-5-036,to R.-H.X.)+2 种基金Natural Science Foundation of Guangdong(2021A1515012439 to M.Z.Q.2021A1515011743 to Q.Z.)Opening Fund of Guangdong Provincial Key Laboratory of Biomedical Imaging(No.GPKLBI202108 of 2018B030322006 to H.Y.Z.)Ministry of Education Frontiers Science Centre for Precision Oncology,University of Macao(SP2023-00001-FSCPO to H.Y.Z.).
文摘Epstein-Barr virus(EBV)-associated gastric cancer(GC)manifests an intriguing immunotherapy response.However,the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined.This study aimed to finely characterize the dynamic tumour immune contexture of human EBV(+)GC treated with immunochemotherapy by longitudinal scRNA-seg and paired scTCR/BCR-seq.EBV(+)GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration.
基金sponsored by Shanghai Junshi Biosciences Co.,Ltd.and supported,in part,by National Key R&D Program of China(2018YFC1313300)Science and Technology Program of Guangdong(2019B020227002)+5 种基金CAMS Innovation Fund for Medical Sciences(2019-I2M-5-036)National Natural Science Foundation of China(81930065)Natural Science Foundation of Guangdong Province(2014A030312015)Science and Technology Program of Guangdong(2019B020227002)Science and Technology Program of Guangzhou(201904020046,201803040019,201704020228)Guangdong Basic and Applied Basic Research Foundation(2019A1515110171).
文摘Background:Several programmed cell death ligand 1(PD-L1)/programmed cell death protein 1(PD-1)antibodies have been approved for cancer treatmentworldwide.Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries,but related data in Chinese patients are limited.This study was conducted to investigate the safety,efficacy,pharmacokinetics,and pharmacodynamics of an anti-PD-1 antibody,toripalimab,in Chinese patients.Methods:A single-center phase I study was conducted in Sun Yat-sen University Cancer Center.Eligible patients were adults with histologically confirmed,treatment-refractory,advanced,solitary malignant tumors.Toripalimab was intravenously infused every 2 weeks in dose-escalating cohorts at 0.3mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg.The study followed standard 3+3 design.Results:Between 15th March 2016 and 27th September 2016,25 patients were enrolled,of whom 3(12.0%),7(28.0%),6(24.0%),6(24.0%),3(12.0%)received 0.3 mg/kg,1 mg/kg,3 mg/kg,10 mg/kg,and 240 mg toripalimab,respectively.After a median follow-up time of 5.0 months(range:1.5-19.8 months),we observed that the commonest treatment-related adverse events(TRAEs)were fatigue(64.0%)and rash(24.0%).No grade 3 or higher TRAEs were observed.No dose-limiting toxicity,treatment-related serious adverse events(SAEs),or treatment-related death occurred.Objective response ratewas 12.5%.The half-life of toripalimabwas 150-222 h after a single dose infusion.Most patients,including those from the 0.3 mg/kg group,maintained complete PD-1 receptor occupancy(>80%)on activated T cells since receiving the first dose of toripalimab.Conclusions:Toripalimab is a promising anti-PD-1 antibody,which was well tolerated and demonstrated anti-tumor activity in treatment-refractory advanced solitary malignant tumors.Further exploration in various tumors and combination therapies is warranted.
文摘1 BACKGROUND With the rapid development of immune checkpoint inhibitors(ICIs)over the past decades,they have become a major area of interest in the treatment of colorectal cancer(CRC)[1,2].There are evidence pointing that programmed cell death protein-1(PD-1)blockade,alone or in combination with anti-cytotoxic T-lymphocyte-associated protein 4(anti-CTLA4)therapy,achieved durable responses in patients with mismatch repair-deficient(dMMR)or microsatellite instability-high(MSI-H)metastatic CRC(mCRC)[3–6].However,the optimal diagnostic method for detecting dMMR/MSI-H disease as well as the optimal anti-PD-1-based treatment modality still remains controversial in this patient subset.In addition,for the majority of mCRC cases that are mismatch repair-proficient(pMMR)or microsatellite stable(MSS),the clinical benefits from these agents are generally minimal[3,7],driving extensive research efforts to develop effective combination therapies in this disease subset.Moreover,investigations of anti-PD-1-based treatments have also been initiated in the nonmetastatic settings of CRC,with some encouraging preliminary evidence[8].Medical oncologists and surgeons from the Committee of Colorectal Cancer of the Chinese Society of Clinical Oncology had a panel discussion on immunotherapy for patients with colorectal cancer during a seminar on June 16,2020,in Guangzhou,China.Herein,the expert opinions have been summarized along with relevant clinical evidence(Table 1)to guide real-world treatment decision-making regarding the use of ICIs in patients with CRC.
文摘Background: Oxaliplatin, irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRINOX) has become one of the first-line treatment options for advanced pancreatic cancer (PC). However, the relatively high rate of grade 3 or 4 adverse events associated with the standard dosage of FOLFIRINOX limits its widespread use in clinical practice. In this study, we were to evaluate the efficacy and safety of a modified FOLFIRINOX regimen as a first-line chemotherapy for Chinese patients with metastatic PC. Methods: Patients with histologically confirmed primary metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 were recruited to receive the modified FOLFIRINOX regimen (intravenous infusion of oxaliplatin, 65 mg/m2;irinotecan, 150 mg/m2;l-leucovorin, 200 mg/ m2;and 5-fluorouracil, 2400 mg/m2, repeated every 2 weeks). The treatment was continued for 12 cycles unless the patient had progressive disease (PD), stable disease (SD) with symptom deterioration, unacceptable adverse events, or requested to terminate the treatment prematurely. The primary endpoint was objective response rate (ORR). Results: Sixty-five patients were enrolled from July 2012 to April 2017 in three institutions, and they all received at least one cycle of chemotherapy, with a median of 8 cycles (range 1-12 cycles). No complete response was observed. Twenty-one (32.3%) patients had partial responses, and 27 (41.5%) had SD. The ORR and disease control rate of the study cohort was 32.3% and 73.8%. The estimated median overall survival and progression-free survival were 11.60 (95% confidence interval [CI] 8.76-14.44) and 5.77 (95% CI 5.00-6.54) months. Major grade 3 or 4 adverse events included neutropenia (12.3%) and diarrhea (6.2%). No treatment-related death was observed. Conclusions: Modified FOLFIRINOX was well-tolerated and might be a promising option as first-line therapy for Chinese patients with metastatic PC.
基金supported by grants from the National Natural Science Foundation of China(81930065,81802971)Science and Technology Program of Guangdong(2019B020227002)+3 种基金Science and Technology Program of Guangzhou(201904020046,201803040019,201704020228)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-036)China Postdoctoral Science Foundation(2018M643301),China Postdoctoral Innovative Talent Support ProgramNatural Science Foundation of Guangdong(2018A0303130282,2019A1515011109).
文摘The acidic tumor microenvironment provides an energy source driving malignant tumor progression.Adaptation of cells to an acidic environment leads to the emergence of cancer stem cells.The expression of the vitamin D receptor(VDR)is closely related to the initiation and development of colorectal carcinoma(CRC),but its regulatory mechanism in CRC stem cells is still unclear.Our study revealed that acidosis reduced VDR expression by downregulating peroxisome proliferator-activated receptor delta(PPARD)expression.Overexpression of VDR effectively suppressed the stemness and oxaliplatin resistance of cells in acidosis.The nuclear export signal in VDR was sensitive to acidosis,and VDR was exported from the nucleus.Chromatin immunoprecipitation(ChIP)and assay for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq)analyses showed that VDR transcriptionally repressed SRY-box 2(SOX2)by binding to the vitamin D response elements in the promoter of SOX2,impairing tumor growth and drug resistance.We demonstrated that a change in the acidic microenvironment combined with overexpression of VDR substantially restricted the occurrence and development of CRC in vivo.These findings reveal a new mechanism by which acidosis could affect the stemness of CRC cells by regulating the expression of SOX2 and show that abnormal VDR expression leads to ineffective activation of vitamin D signaling,resulting in a lack of efficacy of vitamin D in antineoplastic process.
