BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment opti...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment options for liver metastatic PDAC are limited,and chemotherapy alone often proves insufficient.Immunotherapy,particularly programmed cell death 1(PD-1)inhibitors like sintilimab,shows potential efficacy for various cancers but has limited reports on PDAC.This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.AIM To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine(combination group)vs S-1 and gemcitabine used alone(chemotherapy group)for treating liver metastatic pancreatic adenocarcinoma.METHODS Eligible patients were those with only liver metastatic PDAC,an Eastern Cooperative Oncology Group performance status of 0-1,adequate organ and marrow functions,and no prior anticancer therapy.Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks,oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle,and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles or until disease progression,death,or unacceptable toxicity.Participants in the chemotherapy group received oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles.Between June 2020 and December 2021,66 participants were enrolled,with 32 receiving the combination treatment and 34 receiving chemotherapy alone.RESULTS The group receiving the combined therapy exhibited a markedly prolonged median overall survival(18.8 months compared to 10.3 months,P<0.05)and progression-free survival(9.6 months vs 5.4 months,P<0.05).compared to the chemotherapy group.The incidence of severe adverse events did not differ significantly between the two groups(P>0.05).CONCLUSION The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC,meriting further investigation.展开更多
To investigate the protein and mRNA expression of pancreas/duodenal homeobox-1 (PDX-1), a transcription factor as a marker for pancreatic stem cells, in pancreatic ductal cells of rats after partial (90 %) pancreatect...To investigate the protein and mRNA expression of pancreas/duodenal homeobox-1 (PDX-1), a transcription factor as a marker for pancreatic stem cells, in pancreatic ductal cells of rats after partial (90 %) pancreatectomy and evaluated the significance of the PDX-1 expression. Western blot and Reverse transcriptase-polymerase chain reaction (RT-PCR) were used to detect the expression of PDX-1 protein and mRNA respectively. PDX-1 protein was only faintly detected in pancreatic ductal cells on the day 1 after partial pancreatectomy. On the day 2 and 3 after operation in operation group, a 2—3 fold increased PDX-1 protein was observed, corresponding to the characteristic 42—kD protein in Western blot. There was significant difference between operation group and sham-operation group (P<0.05). PDX-1 protein expression on the day 5 and 7 after operation had already been no difference from control group (P>0.05). RT-PCR revealed the PDX-1 mRNA expression showed no significant difference between operation group at various time points and sham-operation group (P>0.05). These results indicate that there was overexpression of PDX-1 in the cells of pancreatic epithelium during the regeneration of remnant pancreas after partial pancreatectomy in adult rats, suggesting the pancreatic stem cells in pancreatic ductal epithelial cells are involved in the regeneration of remnant pancreas and the expression of PDX-1 in ductal cells was regulated posttranscription.展开更多
Background Galectin-1 is aβ-galactoside-binding protein overexpressed in the pancreatic stellate cells(PSCs)of pancreatic ductal adenocarcinoma(PDAC),while its expression is typically low in pancreatic cancer cells(P...Background Galectin-1 is aβ-galactoside-binding protein overexpressed in the pancreatic stellate cells(PSCs)of pancreatic ductal adenocarcinoma(PDAC),while its expression is typically low in pancreatic cancer cells(PCCs).The point at which galectin-1 expression in PCCs increases,and its association with PDAC progression,have been unclear.Methods Galectin-1 expression in PDAC and metastatic lymph nodes was investigated using an immunohistochemical assay.PANC-1 PCC cells were co-cultured with PSCs expressing different levels of galectin-1.Subsequently,galectin-1 was overexpressed in PANC-1 cells using recombinant lentiviruses,and their proliferation,invasion,anchorage-independent growth,and in vivo tumorigenicity were evaluated.Results There was intermediate galectin-1 expression in PCCs,and it was positively associated with galectin-1 expression in PSCs in the PDAC tissues.Galectin-1 was strongly expressed in the metastatic lymph nodes.In the co-culture,high galectin-1 expression in the PSCs increased the galectin-1 expression in the PANC-1 cells.The galectin-1 overexpression in the PANC-1 cells enhanced their clone formation ability,proliferation,and invasion,increased the expression of proliferating cell nuclear antigen(PCNA)and BCL-2,and decreased Bax expression,promoting the establishment and growth of tumors.Conclusion High galectin-1 expression in PSCs induces galectin-1 expression in PCCs and subsequently promotes the malignant biological behavior of PDAC.展开更多
Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC)...Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.展开更多
BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC ...BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment.We describe a case of metastatic PDAC effectively treated with pembrolizumab.CASE SUMMARY We report the case of a 67-year-old woman with unresectable locally advanced PDAC,treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine.At nine months,pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary,confirmed by left lung biopsy.Systemic immunotherapy was then initiated with pembrolizumab,an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types.The patient showed a complete metabolic response that was maintained throughout the treatment.The patient continues to be disease-free at 5.6 years since the start of immunotherapy.CONCLUSION These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC.To our knowledge,this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery.Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.展开更多
Background:The clinical value of heterogeneous sub-populations of circulating tumor cells(CTCs)in pancreatic ductal adenocarcinoma(PDAC)remains unclear.Methods:Peripheral blood samples were obtained from 67 PDAC patie...Background:The clinical value of heterogeneous sub-populations of circulating tumor cells(CTCs)in pancreatic ductal adenocarcinoma(PDAC)remains unclear.Methods:Peripheral blood samples were obtained from 67 PDAC patients.CTCs were isolated by employing CD45 negative enrichment technique and further characterized for epithelial to mesenchymal transition(EMT)or human equilibrative nucleoside transporter-1(hENT-1).The relationships between CTCs sub-phenotypes with clinicopathological factors or post-operative recurrence in PDAC patients were analyzed.Results:EMT related CTCs could be isolated and identified from the 81%of patients(54/67),and both the total count(median:5 vs.17/mL,P<0.0001)and M-CTC percentage(median:0.2 vs.0.345,P=0.0244)of CTCs could differentiate local/regional with metastatic disease.Multivariate analysis showed that both AJCC stage(P=0.025)and M-CTC percentage(P=0.001)were independent prognostic indicators of recurrence free survival(RFS)in resected patients.Moreover,Kaplan-Meier survival analysis showed that M-CTC after 2 courses of chemotherapy was significantly associated with inferior RFS(49.5 weeks vs.undefined,P=0.0288).No significant correlation in hENT-1 expression was found between CTCs and matched tumor tissues,and further multivariate analysis suggested hENT-1 expression in CTCs as independent prognostic factor for RFS(P=0.016).Patients with low hENT-1 expression in CTCs had decreased RFS(32 weeks vs.undefined,P=0.0337).Conclusions:CTCs could be the promising diagnostic biomarkers in PDAC patients,and phenotypic profiling of CTCs based on EMT or hENT-1 could help establish novel prognostic biomarkers in resected patients undergoing adjuvant gemcitabine-based chemotherapy.展开更多
Patients suffering from pancreatic ductal adenocarcinoma (PDAC) have an average survival time of 4 - 6 months after confirmed diagnosis. The primary tumor is surrounded by a thick interstitial fluid with high pressure...Patients suffering from pancreatic ductal adenocarcinoma (PDAC) have an average survival time of 4 - 6 months after confirmed diagnosis. The primary tumor is surrounded by a thick interstitial fluid with high pressure and dense distribution of collagen, forming a huge stroma, rendering the tumor resistant to chemo- and radiotherapy. From the genetic point of view, pancreatic carcinogenesis is driven by mutations, resulting in common activation of the oncogene KRAS, and/or inactivation of one or more of the tumor suppressor genes CDKN2A, TP53, SMAD4 <a href="#ref1">[1]</a>. The pancreas is a mixed exocrine and autocrine organ, with different cell types building up the organ. The pathogenesis involves more than 13 signaling pathways at different stages. Off-balance of the function of the proteins in these pathways due to the stated 4 plus other mutations could readily lead to carcinogenesis. We first present the basic mechanism of these 13 relevant pathways. We then provide a detailed analysis of the progression of this disease, from pancreatitis to tumor formation and metastasis, with special attention on the roles played by the newly discover calcium channel Piezo, stellate cells, stem-cell-like cells, and the concept invadopodium. Thirty potential drugs, based on in vitro and xenograft experiments from different groups, are discussed, including vitamins A, Tocotrienols-E, and D, chemical compounds, non-coding micro RNAs, circular RNA, piwi-interacting RNAs. The recent detection of exosomes enclosing many of these RNAs in body fluids gives us hope of developing early detection methodology because these RNAs carry messages for cell-cell communication at a distance. Delivery of potent drugs by nanoparticles gives us chance to send drugs through the stroma to target the tumor. Since body fluids form a circulating system, together with the connective tissues (where the tumor is associated) form the largest organ—the fascia, we conclude that manifestation of successive pathological states of pancreatic carcinogenesis can be found in compartments of the fascia. We present 17 figures, hoping to ease off the complexity of the pathogenesis of this most lethal cancer disease.展开更多
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly aggressive cancer with poor prognosis.When it metastasizes to the liver,treatment options become particularly limited and challenging.Current treatment options for liver metastatic PDAC are limited,and chemotherapy alone often proves insufficient.Immunotherapy,particularly programmed cell death 1(PD-1)inhibitors like sintilimab,shows potential efficacy for various cancers but has limited reports on PDAC.This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.AIM To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine(combination group)vs S-1 and gemcitabine used alone(chemotherapy group)for treating liver metastatic pancreatic adenocarcinoma.METHODS Eligible patients were those with only liver metastatic PDAC,an Eastern Cooperative Oncology Group performance status of 0-1,adequate organ and marrow functions,and no prior anticancer therapy.Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks,oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle,and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles or until disease progression,death,or unacceptable toxicity.Participants in the chemotherapy group received oral S-140 mg/m²twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m²on days 1 and 8 of the same cycle for up to eight cycles.Between June 2020 and December 2021,66 participants were enrolled,with 32 receiving the combination treatment and 34 receiving chemotherapy alone.RESULTS The group receiving the combined therapy exhibited a markedly prolonged median overall survival(18.8 months compared to 10.3 months,P<0.05)and progression-free survival(9.6 months vs 5.4 months,P<0.05).compared to the chemotherapy group.The incidence of severe adverse events did not differ significantly between the two groups(P>0.05).CONCLUSION The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC,meriting further investigation.
基金ThisprojectwassupportedbyagrantfromNationalNaturalSciencesFoundationofChina (No .30 1 70 91 1 ) .
文摘To investigate the protein and mRNA expression of pancreas/duodenal homeobox-1 (PDX-1), a transcription factor as a marker for pancreatic stem cells, in pancreatic ductal cells of rats after partial (90 %) pancreatectomy and evaluated the significance of the PDX-1 expression. Western blot and Reverse transcriptase-polymerase chain reaction (RT-PCR) were used to detect the expression of PDX-1 protein and mRNA respectively. PDX-1 protein was only faintly detected in pancreatic ductal cells on the day 1 after partial pancreatectomy. On the day 2 and 3 after operation in operation group, a 2—3 fold increased PDX-1 protein was observed, corresponding to the characteristic 42—kD protein in Western blot. There was significant difference between operation group and sham-operation group (P<0.05). PDX-1 protein expression on the day 5 and 7 after operation had already been no difference from control group (P>0.05). RT-PCR revealed the PDX-1 mRNA expression showed no significant difference between operation group at various time points and sham-operation group (P>0.05). These results indicate that there was overexpression of PDX-1 in the cells of pancreatic epithelium during the regeneration of remnant pancreas after partial pancreatectomy in adult rats, suggesting the pancreatic stem cells in pancreatic ductal epithelial cells are involved in the regeneration of remnant pancreas and the expression of PDX-1 in ductal cells was regulated posttranscription.
文摘Background Galectin-1 is aβ-galactoside-binding protein overexpressed in the pancreatic stellate cells(PSCs)of pancreatic ductal adenocarcinoma(PDAC),while its expression is typically low in pancreatic cancer cells(PCCs).The point at which galectin-1 expression in PCCs increases,and its association with PDAC progression,have been unclear.Methods Galectin-1 expression in PDAC and metastatic lymph nodes was investigated using an immunohistochemical assay.PANC-1 PCC cells were co-cultured with PSCs expressing different levels of galectin-1.Subsequently,galectin-1 was overexpressed in PANC-1 cells using recombinant lentiviruses,and their proliferation,invasion,anchorage-independent growth,and in vivo tumorigenicity were evaluated.Results There was intermediate galectin-1 expression in PCCs,and it was positively associated with galectin-1 expression in PSCs in the PDAC tissues.Galectin-1 was strongly expressed in the metastatic lymph nodes.In the co-culture,high galectin-1 expression in the PSCs increased the galectin-1 expression in the PANC-1 cells.The galectin-1 overexpression in the PANC-1 cells enhanced their clone formation ability,proliferation,and invasion,increased the expression of proliferating cell nuclear antigen(PCNA)and BCL-2,and decreased Bax expression,promoting the establishment and growth of tumors.Conclusion High galectin-1 expression in PSCs induces galectin-1 expression in PCCs and subsequently promotes the malignant biological behavior of PDAC.
基金supported by grants from the National Natural Science Foundation of China(81472670,81172005,81402397,81402398 and 81172276)the National Natural Science Foundation of Shanghai(14ZR1407600)+1 种基金the“Yang-Fan”Plan for Young Scientists of Shanghai(14YF1401100)the Ph D Programs Foundation of the Ministry of Education of China(20110071120096)
文摘Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P < 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.
文摘BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment.We describe a case of metastatic PDAC effectively treated with pembrolizumab.CASE SUMMARY We report the case of a 67-year-old woman with unresectable locally advanced PDAC,treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine.At nine months,pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary,confirmed by left lung biopsy.Systemic immunotherapy was then initiated with pembrolizumab,an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types.The patient showed a complete metabolic response that was maintained throughout the treatment.The patient continues to be disease-free at 5.6 years since the start of immunotherapy.CONCLUSION These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC.To our knowledge,this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery.Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.
文摘Background:The clinical value of heterogeneous sub-populations of circulating tumor cells(CTCs)in pancreatic ductal adenocarcinoma(PDAC)remains unclear.Methods:Peripheral blood samples were obtained from 67 PDAC patients.CTCs were isolated by employing CD45 negative enrichment technique and further characterized for epithelial to mesenchymal transition(EMT)or human equilibrative nucleoside transporter-1(hENT-1).The relationships between CTCs sub-phenotypes with clinicopathological factors or post-operative recurrence in PDAC patients were analyzed.Results:EMT related CTCs could be isolated and identified from the 81%of patients(54/67),and both the total count(median:5 vs.17/mL,P<0.0001)and M-CTC percentage(median:0.2 vs.0.345,P=0.0244)of CTCs could differentiate local/regional with metastatic disease.Multivariate analysis showed that both AJCC stage(P=0.025)and M-CTC percentage(P=0.001)were independent prognostic indicators of recurrence free survival(RFS)in resected patients.Moreover,Kaplan-Meier survival analysis showed that M-CTC after 2 courses of chemotherapy was significantly associated with inferior RFS(49.5 weeks vs.undefined,P=0.0288).No significant correlation in hENT-1 expression was found between CTCs and matched tumor tissues,and further multivariate analysis suggested hENT-1 expression in CTCs as independent prognostic factor for RFS(P=0.016).Patients with low hENT-1 expression in CTCs had decreased RFS(32 weeks vs.undefined,P=0.0337).Conclusions:CTCs could be the promising diagnostic biomarkers in PDAC patients,and phenotypic profiling of CTCs based on EMT or hENT-1 could help establish novel prognostic biomarkers in resected patients undergoing adjuvant gemcitabine-based chemotherapy.
文摘Patients suffering from pancreatic ductal adenocarcinoma (PDAC) have an average survival time of 4 - 6 months after confirmed diagnosis. The primary tumor is surrounded by a thick interstitial fluid with high pressure and dense distribution of collagen, forming a huge stroma, rendering the tumor resistant to chemo- and radiotherapy. From the genetic point of view, pancreatic carcinogenesis is driven by mutations, resulting in common activation of the oncogene KRAS, and/or inactivation of one or more of the tumor suppressor genes CDKN2A, TP53, SMAD4 <a href="#ref1">[1]</a>. The pancreas is a mixed exocrine and autocrine organ, with different cell types building up the organ. The pathogenesis involves more than 13 signaling pathways at different stages. Off-balance of the function of the proteins in these pathways due to the stated 4 plus other mutations could readily lead to carcinogenesis. We first present the basic mechanism of these 13 relevant pathways. We then provide a detailed analysis of the progression of this disease, from pancreatitis to tumor formation and metastasis, with special attention on the roles played by the newly discover calcium channel Piezo, stellate cells, stem-cell-like cells, and the concept invadopodium. Thirty potential drugs, based on in vitro and xenograft experiments from different groups, are discussed, including vitamins A, Tocotrienols-E, and D, chemical compounds, non-coding micro RNAs, circular RNA, piwi-interacting RNAs. The recent detection of exosomes enclosing many of these RNAs in body fluids gives us hope of developing early detection methodology because these RNAs carry messages for cell-cell communication at a distance. Delivery of potent drugs by nanoparticles gives us chance to send drugs through the stroma to target the tumor. Since body fluids form a circulating system, together with the connective tissues (where the tumor is associated) form the largest organ—the fascia, we conclude that manifestation of successive pathological states of pancreatic carcinogenesis can be found in compartments of the fascia. We present 17 figures, hoping to ease off the complexity of the pathogenesis of this most lethal cancer disease.
