Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal diseases,with an average 5-year survival rate of less than 10%.Unfortunately,the majority of patients have unresectable,locally advanced,or metastatic di...Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal diseases,with an average 5-year survival rate of less than 10%.Unfortunately,the majority of patients have unresectable,locally advanced,or metastatic disease at the time of diagnosis.Moreover,traditional treatments such as chemotherapy,surgery,and radiation have not been shown to significantly improve survival.Recently,there has been a swift increase in cancer treatments that incorporate immunotherapybased strategies to target all the stepwise events required for tumor initiation and progression.The results in melanoma,non-small-cell lung cancer and renal cell carcinoma are very encouraging.Unfortunately,the application of checkpoint inhibitors,including anti-CTLA4,anti-PD-1,and anti-PD-L1 antibodies,in pancreatic cancer has been disappointing.Many studies have revealed that the PDAC microenvironment supports tumor growth,promotes metastasis and consists of a physical barrier to drug delivery.Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect.In this review,we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist.Particular emphasis is given to the role of the tumor microenvironment,and some of the latest and most promising studies on immunotherapy in PDAC are also presented.展开更多
Objective： To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma （PDAC）. Methods： Parasympathetic neurogene...Objective： To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma （PDAC）. Methods： Parasympathetic neurogenesis was defined as the distribution of abnormal parasympathetic nerves in the stroma tissue. Staining of vesicular acetylcholine transporter （VAChT）, as a marker for parasympathetic neurogenesis, was performed on a representative specimen of the tumor for 59 PDAC patients with available clinical, pathologic, and follow-up information. Three specimens containing normal pancreatic tissues were stained in parallel. The number of parasympathetic nerve fibers was counted in five high-power microscopic fields （5×0.785 mm2）. Cut-offvalues were calculated by receiver operating characteristic curve analysis. Results： VAChT-positive parasympathetic nerve fibers were not seen in the stroma of 3 cases of normal pancreatic tissues. In 59 PDAC cases, the range of parasympathetic neurogenesis was 4-38 fibers/（5×0.785） mm2, with a median of 18 fibers/（5×0.785） mm2. Patients with parasympathetic neurogenesis 〉 15 fibers/（5×0.785） mm2 were defined as the high-density group （39 patients, 66.1%）, and those with parasympathetic neurogenesis 〈15 fibers/（5×0.785） mm2 as the low-density group （20 patients, 33.9%）. The high-density group had a higher occurrence of tumor budding （P=0.001） and a higher rate of early recurrence （P=0.035）. Parasympathetic neurogenesis appeared to be an independent adverse prognostic factor [hazard ratio （HR）=2.45, 95% confidence interval （95% CI）： 1.25-4.81, P=0.009], in addition to American Joint Committee on Cancer （AJCC） stage （P=0.010） and tumor budding （P=0.009）. Conclusions： Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in PDAC.展开更多
目的探讨基于临床病理、乳腺X线(mammography,MG)和MRI特征预测乳腺导管原位癌伴微浸润(ductal carcinoma in situ with microinvasion,DCISM)的价值。材料与方法回顾性收集宁夏医科大学总医院2019年6月至2022年6月最终经手术病理证实...目的探讨基于临床病理、乳腺X线(mammography,MG)和MRI特征预测乳腺导管原位癌伴微浸润(ductal carcinoma in situ with microinvasion,DCISM)的价值。材料与方法回顾性收集宁夏医科大学总医院2019年6月至2022年6月最终经手术病理证实为纯导管原位癌(ductal carcinoma in situ,DCIS)和DCISM的首诊女性患者的病例资料为训练组,评估术前患者的临床病理、MG和MRI特征。采用单、多因素logistic回归分析明确DCISM的独立危险因素,并建立联合模型。通过受试者工作特征(receiver operating characteristic,ROC)曲线下面积(area under the curve,AUC)及校准图评估模型的诊断效能,应用决策曲线分析(decision curve analysis,DCA)观察联合模型的临床实用性。前瞻性收集2022年7月至2023年7月符合纳入、排除标准的患者作为验证组进行验证。应用沙普利加和解释(Shapley Additive exPlanation,SHAP)分析联合模型中病灶最长径、核级别、坏死、Ki-67指数、P63状态、钙化状态和最小ADC值(minimum value of apparent diffusion coefficient,ADCmin)预测DCISM的价值。收集535例患者共550个病灶(15例患者为同时性双乳癌),患者年龄23~81岁,中位年龄50岁。训练组(n=382)中102个病灶(27%)和验证组(n=168)中52个病灶(31%)被诊断为DCISM。结果多因素logistic回归结果显示,病灶最长径、核级别、坏死、Ki-67指数、P63状态、钙化状态和ADCmin是DCISM的独立危险因素。基于上述参数构建临床病理及联合模型,在训练组和验证组中均表现出较高的预测效能(AUC:0.937、0.899)。根据SHAP分析,病灶最长径、Ki-67指数和ADCmin在联合模型中对预测DCISM起主要贡献,而钙化状态、核级别、P63状态和坏死是补充因素。结论联合临床病理及术前MG和MRI特征的预测模型可有效从纯DCIS区分出DCISM,从而提升临床决策和治疗规划的准确性。展开更多
AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells(CTCs) undergoing epithelial-mesenchymal transition(EMT) in pancreatic ductal adenocarcinoma(PDAC) patients.METHODS We identifi...AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells(CTCs) undergoing epithelial-mesenchymal transition(EMT) in pancreatic ductal adenocarcinoma(PDAC) patients.METHODS We identified CTCs for expression of the epithelial cell marker cytokeratin or epithelial cell adhesion molecule(EpCAM)(E-CTC), the mesenchymal cell markers vimentin and twist(M-CTC), or both(E/M-CTC) using the CanPatrol system. Between July 2014 and July 2016, 107 patients with PDAC were enrolled for CTC evaluation. CTC enumeration and classification were correlated with patient clinicopathological features and outcomes.RESULTS CTCs were detected in 78.5% of PDAC patients. The number of total CTCs ranged from 0 to 26 across all 107 patients, with a median value of six. CTC status correlated with lymph node metastasis, TNM stage, distant metastasis, blood lymphocyte counts, and neutrophil-to-lymphocyte ratio(NLR). Kaplan-Meier survival analysis showed that patients with ≥ 6 total CTCs had significantly decreased overall survival and progression-free survival compared with patients with < 6 total CTCs. The presence of M-CTCs was positively correlated with TNM stage(P < 0.01) and distant metastasis(P < 0.01). Additionally, lymphocyte counts and NLR in patients without CTCs were significantly different from those in patients testing positive for each CTC subpopulation(P < 0.01).CONCLUSION Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulations and provides useful evidence for determining a suitable clinical approach.展开更多
Background: MicroRNA?506(miR?506) has been reported to function in several tumors as a tumor suppressor gene or oncogene. However, the expression and role of miR?506 in pancreatic ductal adenocarcinoma(PDAC) remains u...Background: MicroRNA?506(miR?506) has been reported to function in several tumors as a tumor suppressor gene or oncogene. However, the expression and role of miR?506 in pancreatic ductal adenocarcinoma(PDAC) remains unclear. In this study, we aimed to evaluate the phenotype of miR?506 in PDAC.Methods: Using mi RNA in situ hybridization, we examined the expression of miR?506 in 113 PDACs and 87 paired normal pancreatic tissues. We evaluated mi R?506 expression in PDAC cells, normal pancreatic ducts, and acinus/islands, and we analyzed the associations between miR?506 expression and the clinicopathologic characteristics of PDAC patients.Results: miR?506 expression was higher in PDAC than in matched normal pancreatic ductal cells(P < 0.001). On the other hand, the combined group of well and moderately diferentiated PDACs showed higher levels of mi R?506 than the poorly diferentiated ones(P = 0.023). Moreover, mi R?506 expression was negatively associated with pathologic T category(P = 0.004) and lymph node metastasis(P = 0.033), suggesting that mi R?506 might inhibit the progression of PDAC.Conclusions: Our results suggest that mi R?506 either plays a role as an oncogene in the tumorigenesis and a tumor suppressor in the progression or serves as a house?keeping, tumor?suppressing mi RNA, whose expression can be activated by oncogenic signals in early development to hinder the progression of PDAC.展开更多
AIM:To study the indications for sentinel lymph node biopsy(SLNB) in clinically-detected ductal carcinoma in situ(CD-DCIS).METHODS:A retrospective analysis of 20 patients with an initial diagnosis of pure DCIS by an i...AIM:To study the indications for sentinel lymph node biopsy(SLNB) in clinically-detected ductal carcinoma in situ(CD-DCIS).METHODS:A retrospective analysis of 20 patients with an initial diagnosis of pure DCIS by an image-guided core needle biopsy(CNB) between June 2006 and June 2012 was conducted at King Faisal Specialist Hospital.The accuracy of performing SLNB in CD-DCIS,the rate of sentinel and non-sentinel nodal metastasis,and the histologic underestimation rate of invasive cancer at initial diagnosis were analyzed.The inclusion criteria were a preoperative diagnosis of pure DCIS with no evidence of invasion.We excluded any patient with evidence of microinvasion or invasion.There were two cases of mammographically detected DCIS and 18 cases of CDDCIS.All our patients were diagnosed by an imageguided CNB except two patients who were diagnosed by fine needle aspiration(FNA).All patients underwent breast surgery,SLNB,and axillary lymph node dissection(ALND) if the SLN was positive.RESULTS:Twenty patients with an initial diagnosis of pure DCIS underwent SLNB,2 of whom had an ALND.The mean age of the patients was 49.7 years(range,35-70).Twelve patients(60%) were premenopausal and 8(40%) were postmenopausal.CNB was the diagnostic procedure for 18 patients,and 2 who were diagnosed by FNA were excluded from the calculation of the underestimation rate.Two out of 20 had a positive SLNB and underwent an ALND and neither had additional non sentinel lymph node metastasis.Both the sentinel visualization rate and the intraoperative sentinel identification rate were 100%.The false negative rate was 0%.Only 2 patients had a positive SLNB(10%) and neither had additional metastasis following an ALND.After definitive surgery,3 patients were upstaged to invasive ductal carcinoma(3/18 = 16.6%) and 3 other patients were upstaged to DCIS with microinvasion(3/18 = 16.6%).Therefore the histologic underestimation rate of invasive disease was 33%.CONCLUSION:SLNB in CD-DCIS is technically feasible and highly accurate.We recommend limiting SLNB to patients undergoing a mastectomy.展开更多
文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal diseases,with an average 5-year survival rate of less than 10%.Unfortunately,the majority of patients have unresectable,locally advanced,or metastatic disease at the time of diagnosis.Moreover,traditional treatments such as chemotherapy,surgery,and radiation have not been shown to significantly improve survival.Recently,there has been a swift increase in cancer treatments that incorporate immunotherapybased strategies to target all the stepwise events required for tumor initiation and progression.The results in melanoma,non-small-cell lung cancer and renal cell carcinoma are very encouraging.Unfortunately,the application of checkpoint inhibitors,including anti-CTLA4,anti-PD-1,and anti-PD-L1 antibodies,in pancreatic cancer has been disappointing.Many studies have revealed that the PDAC microenvironment supports tumor growth,promotes metastasis and consists of a physical barrier to drug delivery.Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect.In this review,we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist.Particular emphasis is given to the role of the tumor microenvironment,and some of the latest and most promising studies on immunotherapy in PDAC are also presented.
基金supported by grants from China Cancer Research Foundation Y-N2013-008the Doctoral Program of the Ministry of Education 20130001110089 to DR Xiu+1 种基金the National Natural Science Foundation of China 81272709 to W FuPeking University Third Hospital Grant Y81524-01 to LF Zhang
文摘Objective： To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma （PDAC）. Methods： Parasympathetic neurogenesis was defined as the distribution of abnormal parasympathetic nerves in the stroma tissue. Staining of vesicular acetylcholine transporter （VAChT）, as a marker for parasympathetic neurogenesis, was performed on a representative specimen of the tumor for 59 PDAC patients with available clinical, pathologic, and follow-up information. Three specimens containing normal pancreatic tissues were stained in parallel. The number of parasympathetic nerve fibers was counted in five high-power microscopic fields （5×0.785 mm2）. Cut-offvalues were calculated by receiver operating characteristic curve analysis. Results： VAChT-positive parasympathetic nerve fibers were not seen in the stroma of 3 cases of normal pancreatic tissues. In 59 PDAC cases, the range of parasympathetic neurogenesis was 4-38 fibers/（5×0.785） mm2, with a median of 18 fibers/（5×0.785） mm2. Patients with parasympathetic neurogenesis 〉 15 fibers/（5×0.785） mm2 were defined as the high-density group （39 patients, 66.1%）, and those with parasympathetic neurogenesis 〈15 fibers/（5×0.785） mm2 as the low-density group （20 patients, 33.9%）. The high-density group had a higher occurrence of tumor budding （P=0.001） and a higher rate of early recurrence （P=0.035）. Parasympathetic neurogenesis appeared to be an independent adverse prognostic factor [hazard ratio （HR）=2.45, 95% confidence interval （95% CI）： 1.25-4.81, P=0.009], in addition to American Joint Committee on Cancer （AJCC） stage （P=0.010） and tumor budding （P=0.009）. Conclusions： Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in PDAC.
文摘目的探讨基于临床病理、乳腺X线(mammography,MG)和MRI特征预测乳腺导管原位癌伴微浸润(ductal carcinoma in situ with microinvasion,DCISM)的价值。材料与方法回顾性收集宁夏医科大学总医院2019年6月至2022年6月最终经手术病理证实为纯导管原位癌(ductal carcinoma in situ,DCIS)和DCISM的首诊女性患者的病例资料为训练组,评估术前患者的临床病理、MG和MRI特征。采用单、多因素logistic回归分析明确DCISM的独立危险因素,并建立联合模型。通过受试者工作特征(receiver operating characteristic,ROC)曲线下面积(area under the curve,AUC)及校准图评估模型的诊断效能,应用决策曲线分析(decision curve analysis,DCA)观察联合模型的临床实用性。前瞻性收集2022年7月至2023年7月符合纳入、排除标准的患者作为验证组进行验证。应用沙普利加和解释(Shapley Additive exPlanation,SHAP)分析联合模型中病灶最长径、核级别、坏死、Ki-67指数、P63状态、钙化状态和最小ADC值(minimum value of apparent diffusion coefficient,ADCmin)预测DCISM的价值。收集535例患者共550个病灶(15例患者为同时性双乳癌),患者年龄23~81岁,中位年龄50岁。训练组(n=382)中102个病灶(27%)和验证组(n=168)中52个病灶(31%)被诊断为DCISM。结果多因素logistic回归结果显示,病灶最长径、核级别、坏死、Ki-67指数、P63状态、钙化状态和ADCmin是DCISM的独立危险因素。基于上述参数构建临床病理及联合模型,在训练组和验证组中均表现出较高的预测效能(AUC:0.937、0.899)。根据SHAP分析,病灶最长径、Ki-67指数和ADCmin在联合模型中对预测DCISM起主要贡献,而钙化状态、核级别、P63状态和坏死是补充因素。结论联合临床病理及术前MG和MRI特征的预测模型可有效从纯DCIS区分出DCISM,从而提升临床决策和治疗规划的准确性。
文摘AIM To evaluate the clinical properties of three subpopulations of circulating tumor cells(CTCs) undergoing epithelial-mesenchymal transition(EMT) in pancreatic ductal adenocarcinoma(PDAC) patients.METHODS We identified CTCs for expression of the epithelial cell marker cytokeratin or epithelial cell adhesion molecule(EpCAM)(E-CTC), the mesenchymal cell markers vimentin and twist(M-CTC), or both(E/M-CTC) using the CanPatrol system. Between July 2014 and July 2016, 107 patients with PDAC were enrolled for CTC evaluation. CTC enumeration and classification were correlated with patient clinicopathological features and outcomes.RESULTS CTCs were detected in 78.5% of PDAC patients. The number of total CTCs ranged from 0 to 26 across all 107 patients, with a median value of six. CTC status correlated with lymph node metastasis, TNM stage, distant metastasis, blood lymphocyte counts, and neutrophil-to-lymphocyte ratio(NLR). Kaplan-Meier survival analysis showed that patients with ≥ 6 total CTCs had significantly decreased overall survival and progression-free survival compared with patients with < 6 total CTCs. The presence of M-CTCs was positively correlated with TNM stage(P < 0.01) and distant metastasis(P < 0.01). Additionally, lymphocyte counts and NLR in patients without CTCs were significantly different from those in patients testing positive for each CTC subpopulation(P < 0.01).CONCLUSION Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulations and provides useful evidence for determining a suitable clinical approach.
基金supported by the National Natural Science Foundation of China (Nos.81472263 and 81201651)supported by the National Natural Science Foundation of China (No.81472264)+2 种基金a Grant from the Tianjin Municipal Science and Technology Commission (No.14JCYBJC27500)a Grant from the Tianjin Municipal Science and Technology Commission (No.13JCYBJC37400)the National Key Clinical Specialist Construction Programs of China (No.2013?544)
文摘Background: MicroRNA?506(miR?506) has been reported to function in several tumors as a tumor suppressor gene or oncogene. However, the expression and role of miR?506 in pancreatic ductal adenocarcinoma(PDAC) remains unclear. In this study, we aimed to evaluate the phenotype of miR?506 in PDAC.Methods: Using mi RNA in situ hybridization, we examined the expression of miR?506 in 113 PDACs and 87 paired normal pancreatic tissues. We evaluated mi R?506 expression in PDAC cells, normal pancreatic ducts, and acinus/islands, and we analyzed the associations between miR?506 expression and the clinicopathologic characteristics of PDAC patients.Results: miR?506 expression was higher in PDAC than in matched normal pancreatic ductal cells(P < 0.001). On the other hand, the combined group of well and moderately diferentiated PDACs showed higher levels of mi R?506 than the poorly diferentiated ones(P = 0.023). Moreover, mi R?506 expression was negatively associated with pathologic T category(P = 0.004) and lymph node metastasis(P = 0.033), suggesting that mi R?506 might inhibit the progression of PDAC.Conclusions: Our results suggest that mi R?506 either plays a role as an oncogene in the tumorigenesis and a tumor suppressor in the progression or serves as a house?keeping, tumor?suppressing mi RNA, whose expression can be activated by oncogenic signals in early development to hinder the progression of PDAC.
文摘AIM:To study the indications for sentinel lymph node biopsy(SLNB) in clinically-detected ductal carcinoma in situ(CD-DCIS).METHODS:A retrospective analysis of 20 patients with an initial diagnosis of pure DCIS by an image-guided core needle biopsy(CNB) between June 2006 and June 2012 was conducted at King Faisal Specialist Hospital.The accuracy of performing SLNB in CD-DCIS,the rate of sentinel and non-sentinel nodal metastasis,and the histologic underestimation rate of invasive cancer at initial diagnosis were analyzed.The inclusion criteria were a preoperative diagnosis of pure DCIS with no evidence of invasion.We excluded any patient with evidence of microinvasion or invasion.There were two cases of mammographically detected DCIS and 18 cases of CDDCIS.All our patients were diagnosed by an imageguided CNB except two patients who were diagnosed by fine needle aspiration(FNA).All patients underwent breast surgery,SLNB,and axillary lymph node dissection(ALND) if the SLN was positive.RESULTS:Twenty patients with an initial diagnosis of pure DCIS underwent SLNB,2 of whom had an ALND.The mean age of the patients was 49.7 years(range,35-70).Twelve patients(60%) were premenopausal and 8(40%) were postmenopausal.CNB was the diagnostic procedure for 18 patients,and 2 who were diagnosed by FNA were excluded from the calculation of the underestimation rate.Two out of 20 had a positive SLNB and underwent an ALND and neither had additional non sentinel lymph node metastasis.Both the sentinel visualization rate and the intraoperative sentinel identification rate were 100%.The false negative rate was 0%.Only 2 patients had a positive SLNB(10%) and neither had additional metastasis following an ALND.After definitive surgery,3 patients were upstaged to invasive ductal carcinoma(3/18 = 16.6%) and 3 other patients were upstaged to DCIS with microinvasion(3/18 = 16.6%).Therefore the histologic underestimation rate of invasive disease was 33%.CONCLUSION:SLNB in CD-DCIS is technically feasible and highly accurate.We recommend limiting SLNB to patients undergoing a mastectomy.
