Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by abundant granulocytic myeloid-derived suppressor cells (G-MDSC = CD45+/Lin﹣/CD33+/CD11b+/CD15+), which infiltrate tumor...Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by abundant granulocytic myeloid-derived suppressor cells (G-MDSC = CD45+/Lin﹣/CD33+/CD11b+/CD15+), which infiltrate tumors and suppress anti-tumor immunity. We have previously demonstrated in a murine model of PDAC that zoledronic acid (ZA) depletes G-MDSC resulting in decreased tumor growth and improved survival. We report here the results of a phase 1 clinical trial (NCT00892242) using ZA as neo-adjuvant, perioperative therapy in patients with non-metastatic, resectable pancreatic adenocarcinoma. Methods: Eligible PDAC patients received ZA (4 mg) IV 2 weeks prior to surgery. Patients then received 2 additional doses of ZA 4 weeks apart. Blood and bone marrow were obtained from patients prior to treatment with ZA and 3 months after surgery for analysis of G-MDSC by flow cytometry. Results: Twenty-three patients received pre-operative ZA with at least 6 months of follow-up. Only 15 PDAC patients had nonmetastatic PDAC, which was amenable to resection. ZA was well tolerated, and all adverse events were grade 1 or 2. The most common adverse events were fatigue, abdominal pain/discomfort, anorexia, and arthralgia. Of resected PDAC patients treated with ZA, 1- and 2-year overall survival (OS) was 85.7% and 33.3%, respectively, with a median OS of 18 months. This group had a 1- and 2-year progression-free survival (PFS) of 26.9% and 8.9%, respectively, with a median PFS of 12 months. The prevalence of G-MDSC was unchanged in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA. Conclusion: ZA is safe and well tolerated as neo-adjuvant, peri-operative therapy in PDAC patients. In this small study, we did not observe a difference in OS or PFS compared to historical controls. Also, there was no difference in the prevalence of G-MDSC in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor p...Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC.To date,combination chemotherapy remains the mainstay of treatment for most PDAC patients.Compared to other cancer types,treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorterlived.Aside from typically harboring genetic alterations that to date remain undruggable and are drivers of treatment resistance,PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance.However,emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes.These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression.The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells,stromal fibroblasts,and immune cells.This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease.Here,we provide a concise review on lessons learned from past stromatargeting strategies,new challenges revealed from recent preclinical and clinical studies,as well as new prospects in the treatment of PDAC.展开更多
Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma(PDAC).Therapeutics that target the driver mutations,especially the KRAS oncoprotein and its effector cascades,have been ine...Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma(PDAC).Therapeutics that target the driver mutations,especially the KRAS oncoprotein and its effector cascades,have been ineffective.It is increasing clear that the extensive fibro-inflammatory stroma(or desmoplasia)of PDAC plays an active role in the progression and therapeutic resistance of PDAC.The desmoplastic stroma is composed of dense extracellular matrix(ECM)deposited mainly by the cancer-associatedfibroblasts(CAFs)and infiltrated with various types of immune cells.The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells.In addition,mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms,particularly engagement of the epithelial-mesenchymal transition(EMT)program.Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapyinduced apoptosis.Here,we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC.We discussed the experimental models that are currently employed and best suited to study EMT in PDAC,which are instrumental in increasing the chance of successful clinical translation.展开更多
Assessing geographic variations in health events is one of the major tasks in spatial epidemiologic studies. Geographic variation in a health event can be estimated using the neighborhood-level variance that is derive...Assessing geographic variations in health events is one of the major tasks in spatial epidemiologic studies. Geographic variation in a health event can be estimated using the neighborhood-level variance that is derived from a generalized mixed linear model or a Bayesian spatial hierarchical model. Two novel heterogeneity measures, including median odds ratio and interquartile odds ratio, have been developed to quantify the magnitude of geographic variations and facilitate the data interpretation. However, the statistical significance of geographic heterogeneity measures was inaccurately estimated in previous epidemiologic studies that reported two-sided 95% confidence intervals based on standard error of the variance or 95% credible intervals with a range from 2.5th to 97.5th percentiles of the Bayesian posterior distribution. Given the mathematical algorithms of heterogeneity measures, the statistical significance of geographic variation should be evaluated using a one-tailed P value. Therefore, previous studies using two-tailed 95% confidence intervals based on a standard error of the variance may have underestimated the geographic variation in events of their interest and those using 95% Bayesian credible intervals may need to re-evaluate the geographic variation of their study outcomes.展开更多
Neighborhood socioeconomic deprivation has been associated with health behaviors and outcomes. However, neighborhood socioeconomic status has been measured inconsistently across studies. It remains unclear whether app...Neighborhood socioeconomic deprivation has been associated with health behaviors and outcomes. However, neighborhood socioeconomic status has been measured inconsistently across studies. It remains unclear whether appropriate socioeconomic indicators vary over geographic areas and geographic levels. The aim of this study is to compare the composite socioeconomic index to six socioeconomic indicators reflecting different aspects of socioeconomic environment by both geographic areas and levels. Using 2000 U.S. Census data, we performed a multivariate common factor analysis to identify significant socioeconomic resources and constructed 12 composite indexes at the county, the census tract, and the block group levels across the nation and for three states, respectively. We assessed the agreement between composite indexes and single socioeconomic variables. The component of the composite index varied across geographic areas. At a specific geographic region, the component of the composite index was similar at the levels of census tracts and block groups but different from that at the county level. The percentage of population below federal poverty line was a significant contributor to the composite index, regardless of geographic areas and levels. Compared with non-component socioeconomic indicators, component variables were more agreeable to the composite index. Based on these findings, we conclude that a composite index is better as a measure of neighborhood socioeconomic deprivation than a single indicator, and it should be constructed on an area- and unit-specific basis to accurately identify and quantify small-area socioeconomic inequalities over a specific study region.展开更多
Sahin et al.recently reported interim data from a phase 1 clinical trial(NCT02410733)treating melanoma patients with a RNAlipoplex vaccine(RNA-LPX),targeting melanoma TAA.1 The trial is a multicenter,non-randomized,op...Sahin et al.recently reported interim data from a phase 1 clinical trial(NCT02410733)treating melanoma patients with a RNAlipoplex vaccine(RNA-LPX),targeting melanoma TAA.1 The trial is a multicenter,non-randomized,open-label,dose-escalation trial designed to evaluate the safety and tolerability of BNT111 targeting four melanoma TAA(NY-ESO-1,MAGE-A3,tyrosinase,and TPTE).Secondary endpoints include vaccine-induced immune responses and clinical response of patients with measurable disease.展开更多
文摘Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by abundant granulocytic myeloid-derived suppressor cells (G-MDSC = CD45+/Lin﹣/CD33+/CD11b+/CD15+), which infiltrate tumors and suppress anti-tumor immunity. We have previously demonstrated in a murine model of PDAC that zoledronic acid (ZA) depletes G-MDSC resulting in decreased tumor growth and improved survival. We report here the results of a phase 1 clinical trial (NCT00892242) using ZA as neo-adjuvant, perioperative therapy in patients with non-metastatic, resectable pancreatic adenocarcinoma. Methods: Eligible PDAC patients received ZA (4 mg) IV 2 weeks prior to surgery. Patients then received 2 additional doses of ZA 4 weeks apart. Blood and bone marrow were obtained from patients prior to treatment with ZA and 3 months after surgery for analysis of G-MDSC by flow cytometry. Results: Twenty-three patients received pre-operative ZA with at least 6 months of follow-up. Only 15 PDAC patients had nonmetastatic PDAC, which was amenable to resection. ZA was well tolerated, and all adverse events were grade 1 or 2. The most common adverse events were fatigue, abdominal pain/discomfort, anorexia, and arthralgia. Of resected PDAC patients treated with ZA, 1- and 2-year overall survival (OS) was 85.7% and 33.3%, respectively, with a median OS of 18 months. This group had a 1- and 2-year progression-free survival (PFS) of 26.9% and 8.9%, respectively, with a median PFS of 12 months. The prevalence of G-MDSC was unchanged in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA. Conclusion: ZA is safe and well tolerated as neo-adjuvant, peri-operative therapy in PDAC patients. In this small study, we did not observe a difference in OS or PFS compared to historical controls. Also, there was no difference in the prevalence of G-MDSC in the blood and bone marrow of PDAC patients pre- and post-treatment with ZA.
基金National Institutes of Health/National Cancer Institute,No.5R37CA219697-01(to Lim KH)American Cancer Society,No.RSG-17-203-01-TBG(to Lim KH)+1 种基金and Alvin J.Siteman Cancer Center Siteman Investment Program(from Barnard Trust and The Foundation for Barnes-Jewish Hospital)(to Lim KH)and Emerson Collective Grant(to Grierson PM).
文摘Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC.To date,combination chemotherapy remains the mainstay of treatment for most PDAC patients.Compared to other cancer types,treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorterlived.Aside from typically harboring genetic alterations that to date remain undruggable and are drivers of treatment resistance,PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance.However,emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes.These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression.The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells,stromal fibroblasts,and immune cells.This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease.Here,we provide a concise review on lessons learned from past stromatargeting strategies,new challenges revealed from recent preclinical and clinical studies,as well as new prospects in the treatment of PDAC.
基金supported by NIH/NCI R37CA219697-01,WUSTL SPORE Career Enhancement Award grant(1P50CA196510-01A1),American Cancer Society(RSG-17-203-01-TBG),and Alvin J.Siteman Cancer Center Siteman Investment Program(supported by Barnard Trust and The Foundation for Barnes-Jewish Hospital).
文摘Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma(PDAC).Therapeutics that target the driver mutations,especially the KRAS oncoprotein and its effector cascades,have been ineffective.It is increasing clear that the extensive fibro-inflammatory stroma(or desmoplasia)of PDAC plays an active role in the progression and therapeutic resistance of PDAC.The desmoplastic stroma is composed of dense extracellular matrix(ECM)deposited mainly by the cancer-associatedfibroblasts(CAFs)and infiltrated with various types of immune cells.The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells.In addition,mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms,particularly engagement of the epithelial-mesenchymal transition(EMT)program.Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapyinduced apoptosis.Here,we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC.We discussed the experimental models that are currently employed and best suited to study EMT in PDAC,which are instrumental in increasing the chance of successful clinical translation.
文摘Assessing geographic variations in health events is one of the major tasks in spatial epidemiologic studies. Geographic variation in a health event can be estimated using the neighborhood-level variance that is derived from a generalized mixed linear model or a Bayesian spatial hierarchical model. Two novel heterogeneity measures, including median odds ratio and interquartile odds ratio, have been developed to quantify the magnitude of geographic variations and facilitate the data interpretation. However, the statistical significance of geographic heterogeneity measures was inaccurately estimated in previous epidemiologic studies that reported two-sided 95% confidence intervals based on standard error of the variance or 95% credible intervals with a range from 2.5th to 97.5th percentiles of the Bayesian posterior distribution. Given the mathematical algorithms of heterogeneity measures, the statistical significance of geographic variation should be evaluated using a one-tailed P value. Therefore, previous studies using two-tailed 95% confidence intervals based on a standard error of the variance may have underestimated the geographic variation in events of their interest and those using 95% Bayesian credible intervals may need to re-evaluate the geographic variation of their study outcomes.
文摘Neighborhood socioeconomic deprivation has been associated with health behaviors and outcomes. However, neighborhood socioeconomic status has been measured inconsistently across studies. It remains unclear whether appropriate socioeconomic indicators vary over geographic areas and geographic levels. The aim of this study is to compare the composite socioeconomic index to six socioeconomic indicators reflecting different aspects of socioeconomic environment by both geographic areas and levels. Using 2000 U.S. Census data, we performed a multivariate common factor analysis to identify significant socioeconomic resources and constructed 12 composite indexes at the county, the census tract, and the block group levels across the nation and for three states, respectively. We assessed the agreement between composite indexes and single socioeconomic variables. The component of the composite index varied across geographic areas. At a specific geographic region, the component of the composite index was similar at the levels of census tracts and block groups but different from that at the county level. The percentage of population below federal poverty line was a significant contributor to the composite index, regardless of geographic areas and levels. Compared with non-component socioeconomic indicators, component variables were more agreeable to the composite index. Based on these findings, we conclude that a composite index is better as a measure of neighborhood socioeconomic deprivation than a single indicator, and it should be constructed on an area- and unit-specific basis to accurately identify and quantify small-area socioeconomic inequalities over a specific study region.
文摘Sahin et al.recently reported interim data from a phase 1 clinical trial(NCT02410733)treating melanoma patients with a RNAlipoplex vaccine(RNA-LPX),targeting melanoma TAA.1 The trial is a multicenter,non-randomized,open-label,dose-escalation trial designed to evaluate the safety and tolerability of BNT111 targeting four melanoma TAA(NY-ESO-1,MAGE-A3,tyrosinase,and TPTE).Secondary endpoints include vaccine-induced immune responses and clinical response of patients with measurable disease.
