Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibrobl...Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.展开更多
Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,includ...Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.展开更多
Objective:To analyze the efficacy and safety o f apatinib in the treatment of stage IV osteogenic sarcoma after chemotherapy failure through a single-arm,prospective,and open clinical phase II study.Methods:Informatio...Objective:To analyze the efficacy and safety o f apatinib in the treatment of stage IV osteogenic sarcoma after chemotherapy failure through a single-arm,prospective,and open clinical phase II study.Methods:Information on 34 patients with stage IV osteogenic sarcoma treated with apatinib after failure o f chemotherapy in Tianjin Medical University Cancer Institute and Hospital between September 2015 and December 2019 was collected and analyzed.The participants included 23 males and 11 females,with an average age of 35.24 years(11-73 years).The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),PFS rate(PFR),and overall survival(OS)were evaluated.The treatmentrelated adverse events(AEs)and safety of apatinib were also evaluated.Results:O f the 34 patients,33 were able to be evaluated for efficacy.One patient received apatinib treatment for less than one cycle;therefore,only safety analysis was performed.The 12-week clinical evaluation showed that 2 patients had a partial response(PR),24 patients had stable disease(SD),and 7 patients had progressive disease(PD).The ORR,DCR,and PFR at 12 weeks were 6.06%(2/33),78.79%(26/33),and 82%,respectively.By the end of the follow-up,6 patients had SD(18.18%,6/33),27 patients had PD(81.82%,27/33),and 15 patients died because of disease progression(45.45%,15/33).The ORR was 0(0/33),the DCR was 18.18%(6/33),and the median PFS(mPFS)was 7.89 months(95%Cl:4.56-11.21).The median OS(mOS)was 17.61 months(95%Cl:10.85-24.37).The most common treatment-related AEs were hand-foot syndrome(35.29%,12/34),proteinuria(32.35%,11/34),and hypertension(32.35%,11/34).展开更多
Background:Whether non-sentinel lymph node(SLN)-positive melanoma patients can benefit from completion lymph node dissection(CLND)is still unclear.The current study was performed to identify the prognostic role of non...Background:Whether non-sentinel lymph node(SLN)-positive melanoma patients can benefit from completion lymph node dissection(CLND)is still unclear.The current study was performed to identify the prognostic role of nonSLN status in SLN-positive melanoma and to investigate the predictive factors of non-SLN metastasis in acral and cutaneous melanoma patients.Methods:The records of 328 SLN-positive melanoma patients who underwent radical surgery at four cancer centers from September 2009 to August 2017 were reviewed.Clinicopathological data including age,gender,Clark level,Breslow index,ulceration,the number of positive SLNs,non-SLN status,and adjuvant therapy were included for survival analyses.Patients were followed up until death or June 30,2019.Multivariable logistic regression modeling was performed to identify factors associated with non-SLN positivity.Log-rank analysis and Cox regression analysis were used to identify the prognostic factors for disease-free survival(DFS)and overall survival(OS).Results:Among all enrolled patients,220(67.1%)had acral melanoma and 108(32.9%)had cutaneous melanoma.The 5-year DFS and OS rate of the entire cohort was 31.5%and 54.1%,respectively.More than 1 positive SLNs were found in 123(37.5%)patients.Positive non-SLNs were found in 99(30.2%)patients.Patients with positive non-SLNs had significantly worse DFS and OS(log-rank P<0.001).Non-SLN status(P=0.003),number of positive SLNs(P=0.016),and adjuvant therapy(P=0.025)were independent prognostic factors for DFS,while non-SLN status(P=0.002),the Breslow index(P=0.027),Clark level(P=0.006),ulceration(P=0.004),number of positive SLNs(P=0.001),and adjuvant therapy(P=0.007)were independent prognostic factors for OS.The Breslow index(P=0.020),Clark level(P=0.012),and number of positive SLNs(P=0.031)were independently related to positive non-SLNs and could be used to develop more personalized surgical strategy.Conclusions:Non-SLN-positive melanoma patients had worse DFS and OS even after immediate CLND than those with non-SLN-negative melanoma.The Breslow index,Clark level,and number of positive SLNs were independent predictive factors for non-SLN status.展开更多
Dear Editor Pseudomyogenic hemangioendothelioma(PHE)is a newly recognized subtype of hemangioendothelioma characterized by the presence of fibrohistiocytic and myoid cells arranged in a fibroma-like or dermatofibroma-...Dear Editor Pseudomyogenic hemangioendothelioma(PHE)is a newly recognized subtype of hemangioendothelioma characterized by the presence of fibrohistiocytic and myoid cells arranged in a fibroma-like or dermatofibroma-like pattern[1].This rare type of tumor was first named by Hornick and Fletcher[2]and categorized as the novel soft tissue tumor classification system of the World Health Organization in 2013[3].Prior to this,it was referred to as fibroma-like variant of epithelioid sarcoma(ES)and epithelioid sarcoma-like hemangioendothelioma[4].展开更多
基金the National Natural Science Foundation of China(81372872 to J.Yang,81402215 to X.Du,and 81320108022 to K.Chen)funds from the University Cancer Foundation via the Sister Institution Network Fund at the Tianjin Medical University Cancer Institute and Hospital,Fudan University Shanghai Cancer Center,and University of Texas MD Anderson Cancer Centersupported by the program for Innovative Research Team in University in China(IRT1076 to K.Chen)
文摘Low-density lipoprotein receptor-related protein 1(LRP1,also known as CD91),a multifunctional endocytic and cell signaling receptor,is widely expressed on the surface of multiple cell types such as hepatocytes,fibroblasts,neurons,astrocytes,macrophages,smooth muscle cells,and malignant cells.Emerging in vitro and in vivo evidence demonstrates that LRP1 is critically involved in many processes that drive tumorigenesis and tumor progression.For example,LRP1 not only promotes tumor cell migration and invasion by regulating matrix metalloproteinase(MMP)-2and MMP-9 expression and functions but also inhibits cell apoptosis by regulating the insulin receptor,the serine/threonine protein kinase signaling pathway,and the expression of Caspase-3.LRPI-mediated phosphorylation of the extracellular signal-regulated kinase pathway and c-jun N-terminal kinase are also involved in tumor cell proliferation and invasion.In addition,LRP1 has been shown to be down-regulated by microRNA-205 and methylation of LRP1CpG islands.Furthermore,a novel fusion gene,LRP1-SNRNP25,promotes osteosarcoma cell invasion and migration.Only by understanding the mechanisms of these effects can we develop novel diagnostic and therapeutic strategies for cancers mediated by LRP1.
文摘Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.
基金partly supported by the Natural Science Foundation of Tianjin(Grant Nos.16JCYBJC24100 and 18YFZCSY00550).
文摘Objective:To analyze the efficacy and safety o f apatinib in the treatment of stage IV osteogenic sarcoma after chemotherapy failure through a single-arm,prospective,and open clinical phase II study.Methods:Information on 34 patients with stage IV osteogenic sarcoma treated with apatinib after failure o f chemotherapy in Tianjin Medical University Cancer Institute and Hospital between September 2015 and December 2019 was collected and analyzed.The participants included 23 males and 11 females,with an average age of 35.24 years(11-73 years).The objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),PFS rate(PFR),and overall survival(OS)were evaluated.The treatmentrelated adverse events(AEs)and safety of apatinib were also evaluated.Results:O f the 34 patients,33 were able to be evaluated for efficacy.One patient received apatinib treatment for less than one cycle;therefore,only safety analysis was performed.The 12-week clinical evaluation showed that 2 patients had a partial response(PR),24 patients had stable disease(SD),and 7 patients had progressive disease(PD).The ORR,DCR,and PFR at 12 weeks were 6.06%(2/33),78.79%(26/33),and 82%,respectively.By the end of the follow-up,6 patients had SD(18.18%,6/33),27 patients had PD(81.82%,27/33),and 15 patients died because of disease progression(45.45%,15/33).The ORR was 0(0/33),the DCR was 18.18%(6/33),and the median PFS(mPFS)was 7.89 months(95%Cl:4.56-11.21).The median OS(mOS)was 17.61 months(95%Cl:10.85-24.37).The most common treatment-related AEs were hand-foot syndrome(35.29%,12/34),proteinuria(32.35%,11/34),and hypertension(32.35%,11/34).
基金This work was financially supported by the Shanghai Committee of Science and Technology,China(Grant No.19411951700)the Shanghai Anti-cancer Association“Ao Xiang”project(Grant No.SACA-AX112)the National Natural Science Foundation of China(Grant No.81802636).
文摘Background:Whether non-sentinel lymph node(SLN)-positive melanoma patients can benefit from completion lymph node dissection(CLND)is still unclear.The current study was performed to identify the prognostic role of nonSLN status in SLN-positive melanoma and to investigate the predictive factors of non-SLN metastasis in acral and cutaneous melanoma patients.Methods:The records of 328 SLN-positive melanoma patients who underwent radical surgery at four cancer centers from September 2009 to August 2017 were reviewed.Clinicopathological data including age,gender,Clark level,Breslow index,ulceration,the number of positive SLNs,non-SLN status,and adjuvant therapy were included for survival analyses.Patients were followed up until death or June 30,2019.Multivariable logistic regression modeling was performed to identify factors associated with non-SLN positivity.Log-rank analysis and Cox regression analysis were used to identify the prognostic factors for disease-free survival(DFS)and overall survival(OS).Results:Among all enrolled patients,220(67.1%)had acral melanoma and 108(32.9%)had cutaneous melanoma.The 5-year DFS and OS rate of the entire cohort was 31.5%and 54.1%,respectively.More than 1 positive SLNs were found in 123(37.5%)patients.Positive non-SLNs were found in 99(30.2%)patients.Patients with positive non-SLNs had significantly worse DFS and OS(log-rank P<0.001).Non-SLN status(P=0.003),number of positive SLNs(P=0.016),and adjuvant therapy(P=0.025)were independent prognostic factors for DFS,while non-SLN status(P=0.002),the Breslow index(P=0.027),Clark level(P=0.006),ulceration(P=0.004),number of positive SLNs(P=0.001),and adjuvant therapy(P=0.007)were independent prognostic factors for OS.The Breslow index(P=0.020),Clark level(P=0.012),and number of positive SLNs(P=0.031)were independently related to positive non-SLNs and could be used to develop more personalized surgical strategy.Conclusions:Non-SLN-positive melanoma patients had worse DFS and OS even after immediate CLND than those with non-SLN-negative melanoma.The Breslow index,Clark level,and number of positive SLNs were independent predictive factors for non-SLN status.
基金This work was supported by the Key Nature Science Foundation of Tianjin(grant nos.18YFZCSY00550 to Jilong Yang)。
文摘Dear Editor Pseudomyogenic hemangioendothelioma(PHE)is a newly recognized subtype of hemangioendothelioma characterized by the presence of fibrohistiocytic and myoid cells arranged in a fibroma-like or dermatofibroma-like pattern[1].This rare type of tumor was first named by Hornick and Fletcher[2]and categorized as the novel soft tissue tumor classification system of the World Health Organization in 2013[3].Prior to this,it was referred to as fibroma-like variant of epithelioid sarcoma(ES)and epithelioid sarcoma-like hemangioendothelioma[4].
