BACKGROUND Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism(APPM).AIM To understand the prevalence,burden and progression of liver dise...BACKGROUND Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism(APPM).AIM To understand the prevalence,burden and progression of liver disease in patients with APPM including alpha-1 antitrypsin deficiency.METHODS We conducted a retrospective analysis of anonymized patient-level claims data from a German health insurance provider(AOK PLUS).The APPM cohort comprised patients with APPM(identified using the German Modification of the International Classification of Diseases-10th Revision[ICD-10-GM]code E88.0 between 01/01/2010-30/09/2020)and incident liver disease(ICD-10-GM codes K74,K70.2-3 and K71.7 between 01/01/2012-30/09/2020).The control cohort comprised patients without APPM but with incident liver disease.Outcomes were incidence/prevalence of liver disease in patients with APPM,demographics/baseline characteristics,diagnostic procedures,progression-free survival(PFS),disease progression and mortality.RESULTS Overall,2680 and 26299 patients were included in the APPM(fibrosis,96;cirrhosis,2584)and control(fibrosis,1444;cirrhosis,24855)cohorts,respectively.Per 100000 individuals,annual incidence and prevalence of APPM and liver disease was 10-15 and 36-51,respectively.In the APPM cohort,median survival was 4.7 years[95%confidence interval(CI):3.5-7.0]and 2.5 years(95%CI:2.3-2.8)in patients with fibrosis and cirrhosis,respectively.A higher proportion of patients in the APPM cohort experienced disease progression(92.0%)compared with the control cohort(67.2%).Median PFS was shorter in the APPM cohort(0.9 years,95%CI:0.7-1.1)compared with the control cohort(3.7 years,95%CI:3.6-3.8;P<0.001).Patients with cirrhosis in the control cohort had longer event-free survival for ascites,hepatic encephalopathy,hepatic failure and esophageal/gastric varices than patients with cirrhosis in the APPM cohort(P<0.001).Patients with fibrosis in the control cohort had longer event-free survival for ascites,cirrhosis,hepatic failure and esophageal/gastric varices than patients with fibrosis in the APPM cohort(P<0.001).In the APPM cohort,the most common diagnostic procedures within 12 mo after the first diagnosis of liver disease were imaging procedures(66.3%)and laboratory tests(51.0%).CONCLUSION Among patients with liver disease,those with APPM experience substantial burden and earlier liver disease progression than patients without APPM.展开更多
Non-small cell lung cancers (NSCLCs) represent over 80% of all malignant lung tumours and are one of the leading causes of cancer death throughout the world. First- and second-line treatment of advanced or metastatic ...Non-small cell lung cancers (NSCLCs) represent over 80% of all malignant lung tumours and are one of the leading causes of cancer death throughout the world. First- and second-line treatment of advanced or metastatic NSCLCs has changed dramatically during the last two decades with the development of novel immunotherapies (e.g., checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4) sparing NSCLC patients from the toxic effects of chemotherapy. However, only 15% - 20% of all patients respond to treatment. In order to improve response rates, experimental and clinical evidence has provided the basis for further evaluating the combination of co-stimulatory and inhibitory monoclonal antibodies to improve the anti-tumour immune response. Innovative second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I-III trials (either alone or in combination) including the new checkpoint inhibitor target TIGIT (T cell immunoreceptor with Ig and ITIM domains). TIGIT functions as an inhibitory immunoglobin receptor which is overexpressed by different immune cells including effector and memory CD4<sup>+</sup> T and CD8<sup>+</sup> T cells, regulatory T cells (T<sub>regs</sub>), follicular T helper cells (T<sub>fh</sub>), and natural killer cells. Targeting the interaction between the receptors of the TIGIT receptors (e.g., CD96, CD112R, CD226, TIGIT and their corresponding binding partners) has become an innovative strategy for the next concepts of cancer immunotherapy that has the potential to synergize with PD-1/PD-L1checkpoint inhibition. Currently, four anti-TIGIT monoclonal antibodies are currently being studied in phase III trials in NSCLCs: 1) tiragolumab (SKYSCRAPER programme);2) vibostolimab (KEYVIVE programme);3) domvanalimab (ARC programme), and 4) ociperlimab (AdvanTIG programme). The vast majority of these studies are ongoing;however, the SKYSCRAPER-01 trial (tiragolumab in NSCLC) and the SKYSCRAPER-02 trial (tiragolumab in SCLC) were negative and did not meet their primary endpoint. The underlying preclinical and clinical mechanisms of these unexpectedly negative studies are currently far from being clear and the results from currently recruiting clinical studies are eagerly awaited to shed some additional light on these results. From 2021 onwards different TIGIT family receptors are currently evaluated in over 25 clinical trials (phase I-III), however, a lot of preclinical and clinical research is ongoing at different research sites which will help to identify novel immune checkpoint targets with improved activity against malignancies across all histologies.展开更多
Multiple environmental factors impact non-alcoholic fatty liver disease(NAFLD).While the association with dietary habits and physical activity is broadly characterized(1),the contribution of socioeconomic disparities ...Multiple environmental factors impact non-alcoholic fatty liver disease(NAFLD).While the association with dietary habits and physical activity is broadly characterized(1),the contribution of socioeconomic disparities to these risk factors remains elusive to date(2).A cross-sectional study of the National Health and Nutrition Examination Surveys(NHANES)(3)recently examined a cohort representative of the adult U.S.population for combined effects of socio-demographic and lifestyle patterns on NAFLD risk behavior.Physical activity,a high-quality diet and higher education,but not income level,were found to reduce the risk of NALFD,irrespective of ethnicity or gender.As NAFLD is estimated to affect up to a quarter of the global population and particularly become more prevalent in industrialized countries(4),proper characterization of associated population-based risk factors is crucial in optimizing public health and educatory preventive and treatment directives.展开更多
A 25-year-old man with known dermatomyositis was admitted to the University of Leipzig Medical Centre for the first time.The diagnosis was originally made abroad years ago.Current laboratory studies showed elevated C-...A 25-year-old man with known dermatomyositis was admitted to the University of Leipzig Medical Centre for the first time.The diagnosis was originally made abroad years ago.Current laboratory studies showed elevated C-reactive protein and creatine kinase.Antinuclear antibodies,anti-Mi-2 antibodies,anti-Jo-1 antibodies,and anti-Scl-70 antibodies were negative,and the rheumatoid factor was positive.Nailfold video capillaroscopy(NVC)revealed numerous arborized(or“bushy”)capillaries reflecting dermatomyositis-typical neoangiogenesis.Physical examination showed extensive calcinosis cutis on arms,legs,and trunk.展开更多
文摘BACKGROUND Alpha-1 antitrypsin deficiency is a rare genetic disease and a leading cause of inherited alterations in plasma protein metabolism(APPM).AIM To understand the prevalence,burden and progression of liver disease in patients with APPM including alpha-1 antitrypsin deficiency.METHODS We conducted a retrospective analysis of anonymized patient-level claims data from a German health insurance provider(AOK PLUS).The APPM cohort comprised patients with APPM(identified using the German Modification of the International Classification of Diseases-10th Revision[ICD-10-GM]code E88.0 between 01/01/2010-30/09/2020)and incident liver disease(ICD-10-GM codes K74,K70.2-3 and K71.7 between 01/01/2012-30/09/2020).The control cohort comprised patients without APPM but with incident liver disease.Outcomes were incidence/prevalence of liver disease in patients with APPM,demographics/baseline characteristics,diagnostic procedures,progression-free survival(PFS),disease progression and mortality.RESULTS Overall,2680 and 26299 patients were included in the APPM(fibrosis,96;cirrhosis,2584)and control(fibrosis,1444;cirrhosis,24855)cohorts,respectively.Per 100000 individuals,annual incidence and prevalence of APPM and liver disease was 10-15 and 36-51,respectively.In the APPM cohort,median survival was 4.7 years[95%confidence interval(CI):3.5-7.0]and 2.5 years(95%CI:2.3-2.8)in patients with fibrosis and cirrhosis,respectively.A higher proportion of patients in the APPM cohort experienced disease progression(92.0%)compared with the control cohort(67.2%).Median PFS was shorter in the APPM cohort(0.9 years,95%CI:0.7-1.1)compared with the control cohort(3.7 years,95%CI:3.6-3.8;P<0.001).Patients with cirrhosis in the control cohort had longer event-free survival for ascites,hepatic encephalopathy,hepatic failure and esophageal/gastric varices than patients with cirrhosis in the APPM cohort(P<0.001).Patients with fibrosis in the control cohort had longer event-free survival for ascites,cirrhosis,hepatic failure and esophageal/gastric varices than patients with fibrosis in the APPM cohort(P<0.001).In the APPM cohort,the most common diagnostic procedures within 12 mo after the first diagnosis of liver disease were imaging procedures(66.3%)and laboratory tests(51.0%).CONCLUSION Among patients with liver disease,those with APPM experience substantial burden and earlier liver disease progression than patients without APPM.
文摘Non-small cell lung cancers (NSCLCs) represent over 80% of all malignant lung tumours and are one of the leading causes of cancer death throughout the world. First- and second-line treatment of advanced or metastatic NSCLCs has changed dramatically during the last two decades with the development of novel immunotherapies (e.g., checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4) sparing NSCLC patients from the toxic effects of chemotherapy. However, only 15% - 20% of all patients respond to treatment. In order to improve response rates, experimental and clinical evidence has provided the basis for further evaluating the combination of co-stimulatory and inhibitory monoclonal antibodies to improve the anti-tumour immune response. Innovative second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I-III trials (either alone or in combination) including the new checkpoint inhibitor target TIGIT (T cell immunoreceptor with Ig and ITIM domains). TIGIT functions as an inhibitory immunoglobin receptor which is overexpressed by different immune cells including effector and memory CD4<sup>+</sup> T and CD8<sup>+</sup> T cells, regulatory T cells (T<sub>regs</sub>), follicular T helper cells (T<sub>fh</sub>), and natural killer cells. Targeting the interaction between the receptors of the TIGIT receptors (e.g., CD96, CD112R, CD226, TIGIT and their corresponding binding partners) has become an innovative strategy for the next concepts of cancer immunotherapy that has the potential to synergize with PD-1/PD-L1checkpoint inhibition. Currently, four anti-TIGIT monoclonal antibodies are currently being studied in phase III trials in NSCLCs: 1) tiragolumab (SKYSCRAPER programme);2) vibostolimab (KEYVIVE programme);3) domvanalimab (ARC programme), and 4) ociperlimab (AdvanTIG programme). The vast majority of these studies are ongoing;however, the SKYSCRAPER-01 trial (tiragolumab in NSCLC) and the SKYSCRAPER-02 trial (tiragolumab in SCLC) were negative and did not meet their primary endpoint. The underlying preclinical and clinical mechanisms of these unexpectedly negative studies are currently far from being clear and the results from currently recruiting clinical studies are eagerly awaited to shed some additional light on these results. From 2021 onwards different TIGIT family receptors are currently evaluated in over 25 clinical trials (phase I-III), however, a lot of preclinical and clinical research is ongoing at different research sites which will help to identify novel immune checkpoint targets with improved activity against malignancies across all histologies.
文摘Multiple environmental factors impact non-alcoholic fatty liver disease(NAFLD).While the association with dietary habits and physical activity is broadly characterized(1),the contribution of socioeconomic disparities to these risk factors remains elusive to date(2).A cross-sectional study of the National Health and Nutrition Examination Surveys(NHANES)(3)recently examined a cohort representative of the adult U.S.population for combined effects of socio-demographic and lifestyle patterns on NAFLD risk behavior.Physical activity,a high-quality diet and higher education,but not income level,were found to reduce the risk of NALFD,irrespective of ethnicity or gender.As NAFLD is estimated to affect up to a quarter of the global population and particularly become more prevalent in industrialized countries(4),proper characterization of associated population-based risk factors is crucial in optimizing public health and educatory preventive and treatment directives.
文摘A 25-year-old man with known dermatomyositis was admitted to the University of Leipzig Medical Centre for the first time.The diagnosis was originally made abroad years ago.Current laboratory studies showed elevated C-reactive protein and creatine kinase.Antinuclear antibodies,anti-Mi-2 antibodies,anti-Jo-1 antibodies,and anti-Scl-70 antibodies were negative,and the rheumatoid factor was positive.Nailfold video capillaroscopy(NVC)revealed numerous arborized(or“bushy”)capillaries reflecting dermatomyositis-typical neoangiogenesis.Physical examination showed extensive calcinosis cutis on arms,legs,and trunk.
