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.
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
The 2023 update of the Chinese Society of Clinical Oncology(CSCO)Clini-cal Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China,reflecting the latest advancements in evidence-...The 2023 update of the Chinese Society of Clinical Oncology(CSCO)Clini-cal Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China,reflecting the latest advancements in evidence-based medicine,healthcare resource availability,and precision medicine.These updates address the differences in epidemiological characteristics,clinicopatho-logical features,tumor biology,treatment patterns,and drug selections between Eastern and Western gastric cancer patients.Key revisions include a structured template for imaging diagnosis reports,updated standards for molecular marker testing in pathological diagnosis,and an elevated recommendation for neoadju-vant chemotherapy in stage III gastric cancer.For advanced metastatic gastric cancer,the guidelines introduce new recommendations for immunotherapy,anti-angiogenic therapy and targeted drugs,along with updated management strategies for human epidermal growth factor receptor 2(HER2)-positive and deficient DNA mismatch repair(dMMR)/microsatellite instability-high(MSI-H)patients.Additionally,the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer.The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice,particularly in the heterogeneous healthcare landscape of China,while maintaining a commitment to scientific rigor,impartiality,and timely revisions.展开更多
There exist differences in the epidemiological characteristics,clinicopathological features,tumor biological characteristics,treatment patterns,and drug selections between gastric cancer patients from the Eastern and ...There exist differences in the epidemiological characteristics,clinicopathological features,tumor biological characteristics,treatment patterns,and drug selections between gastric cancer patients from the Eastern and Western countries.The Chinese Society of Clinical Oncology(CSCO)has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually.Taking into account regional differences,giving full consideration to the accessibility of diagnosis and treatment resources,these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China.The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis,treatment,follow-up,and screening of gastric cancer.Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines,this updated guideline integrates the results ofmajor clinical studies from China and overseas for the past year,focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations.For the comprehensive treatment of non-metastatic gastric cancer,attentions were paid to neoadjuvant treatment.The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated.For the comprehensive treatment of metastatic gastric cancer,recommendations for immunotherapy were included,and immune checkpoint inhibitors fromthird-line to the first-line of treatment for different patient groups with detailed notes are provided.展开更多
Metabolic enzymes have an indispensable role in metabolic reprogramming,and their aberrant expression or activity has been associated with chemosensitivity.Hence,targeting metabolic enzymes remains an attractive appro...Metabolic enzymes have an indispensable role in metabolic reprogramming,and their aberrant expression or activity has been associated with chemosensitivity.Hence,targeting metabolic enzymes remains an attractive approach for treating tumors.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
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
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
This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxal...This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment forunresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologicallyconfirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients receivedSHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m^(2)) intravenously on day 1, along with oral capecitabine(1 g/m^(2) twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenancetherapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) perRECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival(PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% ofpatients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that hightumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactatedehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safetyprofile and potent antitumor activity in unresectable mCRC.展开更多
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.
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
文摘The 2023 update of the Chinese Society of Clinical Oncology(CSCO)Clini-cal Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China,reflecting the latest advancements in evidence-based medicine,healthcare resource availability,and precision medicine.These updates address the differences in epidemiological characteristics,clinicopatho-logical features,tumor biology,treatment patterns,and drug selections between Eastern and Western gastric cancer patients.Key revisions include a structured template for imaging diagnosis reports,updated standards for molecular marker testing in pathological diagnosis,and an elevated recommendation for neoadju-vant chemotherapy in stage III gastric cancer.For advanced metastatic gastric cancer,the guidelines introduce new recommendations for immunotherapy,anti-angiogenic therapy and targeted drugs,along with updated management strategies for human epidermal growth factor receptor 2(HER2)-positive and deficient DNA mismatch repair(dMMR)/microsatellite instability-high(MSI-H)patients.Additionally,the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer.The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice,particularly in the heterogeneous healthcare landscape of China,while maintaining a commitment to scientific rigor,impartiality,and timely revisions.
文摘There exist differences in the epidemiological characteristics,clinicopathological features,tumor biological characteristics,treatment patterns,and drug selections between gastric cancer patients from the Eastern and Western countries.The Chinese Society of Clinical Oncology(CSCO)has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually.Taking into account regional differences,giving full consideration to the accessibility of diagnosis and treatment resources,these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China.The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis,treatment,follow-up,and screening of gastric cancer.Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines,this updated guideline integrates the results ofmajor clinical studies from China and overseas for the past year,focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations.For the comprehensive treatment of non-metastatic gastric cancer,attentions were paid to neoadjuvant treatment.The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated.For the comprehensive treatment of metastatic gastric cancer,recommendations for immunotherapy were included,and immune checkpoint inhibitors fromthird-line to the first-line of treatment for different patient groups with detailed notes are provided.
基金This research was supported by the National Natural Science Foundation of China(82022052,82173128,81930065,82073377,81772587)Natural Science Foundation of Guangdong Province(2018B030306049,2021A1515012439)Science and Technology Program of Guangdong(2019B020227002)+1 种基金Science and Technology Program of Guangzhou(201904020046)CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-036).
文摘Metabolic enzymes have an indispensable role in metabolic reprogramming,and their aberrant expression or activity has been associated with chemosensitivity.Hence,targeting metabolic enzymes remains an attractive approach for treating tumors.
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.
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.
基金supported by Jiangsu Hengrui Pharmaceuticals and the following grants:the National Natural Science Foundation of China(NSFC:82321003,82173128,82073377,81930065)the Natural Science Foundation of Guangdong(2021A1515012439)+2 种基金Guangdong Basic and Applied Basic Research Foundation(2024B1515020120)the CAMS Innovation Fund for Medical Sciences(CIFMS:2019-I2M-5-036)Additional funding was provided by the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0004).
文摘This phase 2/3 trial (NCT04856787) assessed the efficacy and safety of SHR-1701, a bifunctional protein targeting PD-L1 and TGF-β,in combination with BP102 (a bevacizumab biosimilar) and XELOX (capecitabine plus oxaliplatin) as a first-line treatment forunresectable metastatic colorectal cancer (mCRC). In this phase 2 study, a total of 62 patients with untreated, histologicallyconfirmed colorectal adenocarcinoma and no prior systemic therapy for metastatic disease were enrolled. Patients receivedSHR-1701 (30 mg/kg), bevacizumab (7.5 mg/kg), and oxaliplatin (130 mg/m^(2)) intravenously on day 1, along with oral capecitabine(1 g/m^(2) twice daily) on days 1-14 of 21-day cycles. Up to eight induction cycles were administered, followed by maintenancetherapy for responders or those with stable disease. The primary endpoints were safety and objective response rate (ORR) perRECIST v1.1. The combination achieved an ORR of 59.7% and a disease control rate (DCR) of 83.9%. Median progression-free survival(PFS) was 10.3 months (95% CI: 8.3-13.7), with 6- and 12-month PFS rates of 77.2% and 41.3%, respectively. The estimated12-month overall survival (OS) rate was 67.7%. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 59.7% ofpatients, with anemia and neutropenia (8.1% each) being the most common. Retrospective DNA sequencing revealed that hightumor mutational burden, neo-antigens, and SBS15 enrichment correlated with better responses. Elevated baseline lactatedehydrogenase was linked to shorter PFS. SHR-1701 combined with XELOX and bevacizumab demonstrated a manageable safetyprofile and potent antitumor activity in unresectable mCRC.
