Background The identification of modifiable bleeding risk factors may be of relevance.The aim is to evaluate if aortic stenosis(AS)provides additional information to bleeding risk scores for predicting major bleeding(...Background The identification of modifiable bleeding risk factors may be of relevance.The aim is to evaluate if aortic stenosis(AS)provides additional information to bleeding risk scores for predicting major bleeding(MB)in non-valvular atrial fibrillation(AF).Methods We designed a retrospective multi-center study including 2880 consecutive non-valvular AF patients initiating oral anticoagulation between January 2013 and December 2016.AS was defined as moderate or severe according to European echocardiography guidelines criteria.HASBLED,ATRIA and ORBIT scores were used to evaluate the bleeding risk.MB was defined according to the International Society on Thrombosis and Haemostasia criteria and registered at 18 months of follow-up.Results 168(5.8%)patients had AS.Patients with AS had higher risk for MB compared to those without AS(HR=2.13,95%CI:1.40-3.23,P<0.001).Patients without AS and low-intermediate bleeding risk(0 points)showed the lowest MB rate,whereas the MB rate observed among patients with AS and high bleeding risk(2 points)was the highest one.Discrimination and reclassification analyses showed that AS provided additional information to bleeding risk scores for predicting MB at 18 months of follow-up.Conclusions In this population,AS was associated with an increased risk for MB at midterm follow-up.The three scoring systems showed a moderate discriminatory ability for MB.Moreover,the addition of AS was associated with a significant improvement in their predictive accuracy.We suggest that the presence of this valvulopathy should be taken into account for bleeding risk assessment.展开更多
Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (U...Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8<sup>+</sup> cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4<sup>+</sup> T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells’ function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.展开更多
Post-traumatic hepatic artery pseudoaneurysm is unc-ommon,appearing in approximately 1%of hepatic trauma cases.Most are extrahepatic(80%)and have a late onset.Although they are usually asymptomatic, they should always...Post-traumatic hepatic artery pseudoaneurysm is unc-ommon,appearing in approximately 1%of hepatic trauma cases.Most are extrahepatic(80%)and have a late onset.Although they are usually asymptomatic, they should always be treated becasue of the high risk of complications,especially breakage.Currently the treatment of choice is endovascular embolization with coils or the exclusion of the pseudoaneurysm using other intravascular devices.Recently there have been accounts of a treatment that combines embolization with coils and image-guided percutaneous human thrombin injection.We present a case of post-traumatichepatic artery pseudoaneurysm that was successfully treated using this combined technique.展开更多
Transplantation is the optimal treatment for end-stage organ failure,and modern immunosuppression has allowed important progress in short-term outcomes. However,immunosuppression poorly influences chronic rejection an...Transplantation is the optimal treatment for end-stage organ failure,and modern immunosuppression has allowed important progress in short-term outcomes. However,immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus,a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor Fox P3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise,other immune cells,such as dendritic cells,monocyte/macrophages or natural killer cells,have been described as part of the process known as "operational tolerance". However,translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way,a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multicenter clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.展开更多
Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular function...Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.展开更多
We have read with great interest the recent study published by Li et al.,entitled“Associating liver partition and portal vein ligation for staged hepatectomy versus sequential transarterial chemoembolization and port...We have read with great interest the recent study published by Li et al.,entitled“Associating liver partition and portal vein ligation for staged hepatectomy versus sequential transarterial chemoembolization and portal vein embolization in staged hepatectomy for HBV-related hepatocellular carcinoma:a randomized comparative study”(1).展开更多
Objective To assess the differences in incidence, clinical features, current treatment strategies and outcome in patients with type-2vs. type-1 acute myocardial infarction （AMI）.Methods We included 824 consecutive p...Objective To assess the differences in incidence, clinical features, current treatment strategies and outcome in patients with type-2vs. type-1 acute myocardial infarction （AMI）.Methods We included 824 consecutive patients with a diagnosis of type-1 or type-2 AMI. Dur-ing index hospitalization, clinical features and treatment strategies were collected in detail. At 1-year follow-up, mortality, stroke, non-fatal myocardial infarction and major bleeding were recorded.ResultsType-1 AMI was present in 707 （86%） of the cases while 117 （14%） were classified as type-2. Patients with type-2 AMI were more frequently female and had higher co-morbidities such as diabetes, previous non-ST segment elevation acute coronary syndromes, impaired renal function, anaemia, atrial fibrillation and malignancy. However, preserved left ventricular ejection fraction and normal coronary arteries were more frequently seen, an invasive treatment was less common, and anti-platelet medications, statins and beta-blockers were less prescribed in patients with type-2 AMI. At 1-year follow-up, type-2 AMI was associated with a higher crude mortality risk （HR： 1.75, 95% CI： 1.14-2.68;P = 0.001）, but this association did not remain significant after multivariable adjustment （P = 0.785）. Furthermore, we did not find type-2 AMI to be associated with other clinical outcomes.Conclusions In this real-life population, compared with type-1, type-2 AMI were predominantly women and had more co-morbidities. Invasive treatment strategies and cardioprotective medications were less used in type-2, while the 1-year clinical outcomes were similar.展开更多
AIM:To evaluates the effectiveness and safety of the first generation,NS3/4A protease inhibitors(PIs) in clinical practice against chronic C virus,especially in patients with advanced fibrosis. METHODS:Prospective stu...AIM:To evaluates the effectiveness and safety of the first generation,NS3/4A protease inhibitors(PIs) in clinical practice against chronic C virus,especially in patients with advanced fibrosis. METHODS:Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1,treatment-na?ve(TN) or treatment-experienced(TE),who underwent triple therapy with the first generation NS3/4A protease inhibitors,boceprevir(BOC) and telaprevir(TVR),in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up.RESULTS:One thousand and fifty seven patients were included,405(38%) were treated with BOC and 652(62%) with TVR. Of this total,30%(n = 319) were TN and the remaining were TE:28%(n = 298) relapsers,12%(n = 123) partial responders(PR),25%(n = 260) null-responders(NR) and for 5%(n = 57) with prior response unknown. The rate of sustained virologic response(SVR) by intention-to-treatment(ITT) was greater in those treated with TVR(65%) than in those treated with BOC(52%)(P < 0.0001),whereas by modified intention-to-treatment(m ITT) no were found significant differences. By degree of fibrosis,56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients,both TN and TE. In the analysis by groups,the TN patients treated with TVR by ITT showed a higher SVR(P = 0.005). However,by m ITT there were no significant differences between BOC and TVR. In the multivariate analysis by m ITT,the significant SVR factors were relapsers,IL28 B CC and non-F4; the type of treatment(BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients,treated with BOC(46%) or with TVR(45%). 28% of the patients interrupted the treatment,mainly by non-viral response(51%):this outcome was more frequent in the TE than in the TN patients(57% vs 40%,P = 0.01). With respect to severe haematological disorders,neutropaenia was more likely to affect the patients treated with BOC(33% vs 20%,P ≤ 0.0001),and thrombocytopaenia and anaemia,the F4 patients(P = 0.000,P = 0.025,respectively). CONCLUSION:In a real clinical practice setting with a high proportion of patients with advanced fibrosis,effectiveness of first-generation PIs was high except for NR patients,with similar SVR rates being achieved by BOC and TVR.展开更多
Background:The use of laparoscopic(LLR)and robotic liver resections(RLR)has been safely performed in many institutions for liver tumours.A large scale international multicenter study would provide stronger evidence an...Background:The use of laparoscopic(LLR)and robotic liver resections(RLR)has been safely performed in many institutions for liver tumours.A large scale international multicenter study would provide stronger evidence and insight into application of these techniques for huge liver tumours≥10 cm.Methods:This was a retrospective review of 971 patients who underwent LLR and RLR for huge(≥10 cm)tumors at 42 international centers between 2002-2020.Results:One hundred RLR and 699 LLR which met study criteria were included.The comparison between the 2 approaches for patients with huge tumors were performed using 1:3 propensity-score matching(PSM)(73 vs.219).Before PSM,LLR was associated with significantly increased frequency of previous abdominal surgery,malignant pathology,liver cirrhosis and increased median blood.After PSM,RLR and LLR was associated with no significant difference in key perioperative outcomes including media operation time(242 vs.290 min,P=0.286),transfusion rate rate(19.2%vs.16.9%,P=0.652),median blood loss(200 vs.300 mL,P=0.694),open conversion rate(8.2%vs.11.0%,P=0.519),morbidity(28.8%vs.21.9%,P=0.221),major morbidity(4.1%vs.9.6%,P=0.152),mortality and postoperative length of stay(6 vs.6 days,P=0.435).Conclusions:RLR and LLR can be performed safely for selected patients with huge liver tumours with excellent outcomes.There was no significant difference in perioperative outcomes after RLR or LLR.展开更多
The characterization and isolation of various stem cell populations, from embryonic to tissue-derived stem cells and induced pluripotent stem cells (iPSCs), have led to a rapid growth in the field of stem cell researc...The characterization and isolation of various stem cell populations, from embryonic to tissue-derived stem cells and induced pluripotent stem cells (iPSCs), have led to a rapid growth in the field of stem cell research and its potentially clinical application in the field of regenerative medicine and tissue repair. Stem cell therapy has recently progressed from the preclinical to the early clinical trial arena for a variety of diseases states, although further knowledge on action mechanisms, long-term safety issues, and standardization and characterization of the therapeutic cell products remains to be thoroughly elucidated. In this paper we summarize the current state of the art of basic and clinical research that were highlighted at the 2012 meeting of the Spanish Cell Therapy Network. This includes the current research involving in genomic and transcriptomic characterization of selected stem cell populations, studies of the role of resident and transplanted stem cells during tissue regeneration and their mechanism of action, improved new strategies of tissue engineering, transplantation of mesenchymal stem cells (MSCs) in different animal models of disease, disease correction by iPSCs, and preliminary results of cell therapy in human clinical trials.展开更多
Cyclin-dependent kinases 4 and 6(CDK4/6)inhibitors demonstrated activity in terms of progression-free survival(PFS)in advanced dedifferentiated liposarcoma(DD-LPS),a sarcoma with CDK4 amplification.CDK4 overexpression...Cyclin-dependent kinases 4 and 6(CDK4/6)inhibitors demonstrated activity in terms of progression-free survival(PFS)in advanced dedifferentiated liposarcoma(DD-LPS),a sarcoma with CDK4 amplification.CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors.Preclinical investigators of this study found that CDK4 overexpression,while not of CDKN2A,was the most consistent predictive factor for palbociclib efficacy in sarcomas.Advanced adult-type soft-tissue sarcoma,excluding DD-LPS,or bone sarcoma patients,progressing after at least one systemic line,whose tumors overexpressed CDK4,but not CDKN2A at baseline biopsy,were accrued in this single-arm phase II trial(EudraCT number:2016-004039-19).With the main endpoint of a 6-month PFS rate,40%was considered promising in this population.Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles.A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening,archival material(141),and screening,baseline biopsy(95).There were 28(29%)with favorable mRNA profiles from 95 screened patients at baseline.From 23 enrolled patients,21 evaluable,the 6-month PFS rate was 29%(95%CI 9–48),and there were 6 patients out of 21 with a PFS longer than 6 months.The median PFS and overall survival were 4.2(95%CI 3.6–4.8)and 12(95%CI 8.7–15.4)months,respectively.Translational research showed a significant correlation between CDK4 mRNA and protein expression.Palbociclib was active in a variety of sarcoma subtypes,selected by CDK4/CDKN2A,and deserves further investigation in the sarcoma context.展开更多
In the liver surgical oncology,a complete resection of the primary or metastatic liver tumors remains the main objective.If the tumor invades the hepatic vein or the inferior vena cava(IVC)a curative resection becomes...In the liver surgical oncology,a complete resection of the primary or metastatic liver tumors remains the main objective.If the tumor invades the hepatic vein or the inferior vena cava(IVC)a curative resection becomes challenging.However,recent advances in intraoperative hemodynamic management together with the refinement of the surgical technique acquired by complex liver surgery and transplantation have allowed to perform hepatic vein or vena cava resection for curation with low morbidity and mortality.展开更多
Background and purpose Spain has been heavily affected by COVID-19.Reallocation of resources for managing the outbreak might have caused a disruption in stroke care.This study analyses the impact on stroke care of reo...Background and purpose Spain has been heavily affected by COVID-19.Reallocation of resources for managing the outbreak might have caused a disruption in stroke care.This study analyses the impact on stroke care of reorganising the healthcare system in response to the first COVID-19 outbreak peak in Spain and the strategies adopted by Spanish stroke units to deal with this impact.Materials and methods We obtained data from a structured survey sent to the responsible of stroke units across the country.We recorded the number of strokes,stroke code activations,intravenous thrombolysis treatments and mechanical thrombectomies during February and March 2019 and 2020.We also collected information on the impact on workflow metrics and on the availability of specialised neurological care and rehabilitation treatments,the characteristics of stroke care for patients with SARS-CoV-2 infection and the impact on human resources.We compared the activity data between 2019 and 2020 and the information on activity and impact on stroke care between regions classified according to the disease incidence rate.Results Fifty-seven(75%)of all stroke units in Spain responded to the survey.There was an overall reduction in admissions for all stroke types during the outbreak’s peak and in the number of stroke code activations and intravenous thrombolysis treatments,results that were independent of the COVID-19 incidence rate.Participants reported a delay in workflow metrics and a reduction of admissions to stroke units,outpatient clinics and rehabilitation therapies.Specific pathways and protocols for managing stroke patients with SARS-CoV-2 infection have been established.Conclusion The COVID-19 outbreak has jeopardised all phases of stroke care.As a consequence,some patients with stroke did not receive adequate treatment.展开更多
文摘Background The identification of modifiable bleeding risk factors may be of relevance.The aim is to evaluate if aortic stenosis(AS)provides additional information to bleeding risk scores for predicting major bleeding(MB)in non-valvular atrial fibrillation(AF).Methods We designed a retrospective multi-center study including 2880 consecutive non-valvular AF patients initiating oral anticoagulation between January 2013 and December 2016.AS was defined as moderate or severe according to European echocardiography guidelines criteria.HASBLED,ATRIA and ORBIT scores were used to evaluate the bleeding risk.MB was defined according to the International Society on Thrombosis and Haemostasia criteria and registered at 18 months of follow-up.Results 168(5.8%)patients had AS.Patients with AS had higher risk for MB compared to those without AS(HR=2.13,95%CI:1.40-3.23,P<0.001).Patients without AS and low-intermediate bleeding risk(0 points)showed the lowest MB rate,whereas the MB rate observed among patients with AS and high bleeding risk(2 points)was the highest one.Discrimination and reclassification analyses showed that AS provided additional information to bleeding risk scores for predicting MB at 18 months of follow-up.Conclusions In this population,AS was associated with an increased risk for MB at midterm follow-up.The three scoring systems showed a moderate discriminatory ability for MB.Moreover,the addition of AS was associated with a significant improvement in their predictive accuracy.We suggest that the presence of this valvulopathy should be taken into account for bleeding risk assessment.
基金Supported by The Projects from Foundation Seneca,No.05748/PI/07 and No.04487/GERM/06the Fondo de Investigación Sanitaria(FIS)projects CIBERehd,No.PI11/02644 and No.PI11/02686(in part)the ISCⅡ and Fundación para la Formación e Investigación Sanitarias de la Región de Murcia(FFIS),No.CA11/00034(to López-Hernández R)
文摘Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn’s disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8<sup>+</sup> cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4<sup>+</sup> T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells’ function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.
基金Supported by Departments of Radiology and Surgery at University general hospital Virgen de la Arrixaca
文摘Post-traumatic hepatic artery pseudoaneurysm is unc-ommon,appearing in approximately 1%of hepatic trauma cases.Most are extrahepatic(80%)and have a late onset.Although they are usually asymptomatic, they should always be treated becasue of the high risk of complications,especially breakage.Currently the treatment of choice is endovascular embolization with coils or the exclusion of the pseudoaneurysm using other intravascular devices.Recently there have been accounts of a treatment that combines embolization with coils and image-guided percutaneous human thrombin injection.We present a case of post-traumatichepatic artery pseudoaneurysm that was successfully treated using this combined technique.
基金Supported by the Fondo de Investigaciones Sanitarias Grants,No.PI12/02042
文摘Transplantation is the optimal treatment for end-stage organ failure,and modern immunosuppression has allowed important progress in short-term outcomes. However,immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus,a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor Fox P3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise,other immune cells,such as dendritic cells,monocyte/macrophages or natural killer cells,have been described as part of the process known as "operational tolerance". However,translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way,a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multicenter clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.
基金Supported by Novartis Espana and by grant to Pons JA as Principal Investigator from Instituto Salud Carlos III,No.PI12/02042
文摘Mammalian target of rapamycin, also known as me-chanistic target of rapamycin(m TOR) is a protein kinase that belongs to the PI3K/AKT/m TOR signaling pathway, which is involved in several fundamental cellular functions such as cell growth, proliferation, and survival. This protein and its associated pathway have been implicated in cancer development and the regulation of immune responses, including the rejection response generated following allograft transplantation. Inhibitors of m TOR(m TORi) such as rapamycin and its derivative everolimus are potent immunosuppressive drugs that both maintain similar rates of efficacy and could optimize the renal function and diminish the side effects compared with calcineurin inhibitors. These drugs are used in solid-organ transplantationtoinduceimmunosuppression while also promoting the expansion of CD4+CD25+FOXP3+ regulatory T-cells that could favor a scenery of immu-nological tolerance. In this review, we describe the mechanisms by which inhibitors of m TOR induce sup-pression by regulation of these pathways at different levels of the immune response. In addition, we par-ticularly emphasize about the main methods that are used to assess the potency of immunosuppressive drugs, highlighting the studies carried out about immunosuppressive potency of inhibitors of m TOR.
文摘We have read with great interest the recent study published by Li et al.,entitled“Associating liver partition and portal vein ligation for staged hepatectomy versus sequential transarterial chemoembolization and portal vein embolization in staged hepatectomy for HBV-related hepatocellular carcinoma:a randomized comparative study”(1).
文摘Objective To assess the differences in incidence, clinical features, current treatment strategies and outcome in patients with type-2vs. type-1 acute myocardial infarction （AMI）.Methods We included 824 consecutive patients with a diagnosis of type-1 or type-2 AMI. Dur-ing index hospitalization, clinical features and treatment strategies were collected in detail. At 1-year follow-up, mortality, stroke, non-fatal myocardial infarction and major bleeding were recorded.ResultsType-1 AMI was present in 707 （86%） of the cases while 117 （14%） were classified as type-2. Patients with type-2 AMI were more frequently female and had higher co-morbidities such as diabetes, previous non-ST segment elevation acute coronary syndromes, impaired renal function, anaemia, atrial fibrillation and malignancy. However, preserved left ventricular ejection fraction and normal coronary arteries were more frequently seen, an invasive treatment was less common, and anti-platelet medications, statins and beta-blockers were less prescribed in patients with type-2 AMI. At 1-year follow-up, type-2 AMI was associated with a higher crude mortality risk （HR： 1.75, 95% CI： 1.14-2.68;P = 0.001）, but this association did not remain significant after multivariable adjustment （P = 0.785）. Furthermore, we did not find type-2 AMI to be associated with other clinical outcomes.Conclusions In this real-life population, compared with type-1, type-2 AMI were predominantly women and had more co-morbidities. Invasive treatment strategies and cardioprotective medications were less used in type-2, while the 1-year clinical outcomes were similar.
文摘AIM:To evaluates the effectiveness and safety of the first generation,NS3/4A protease inhibitors(PIs) in clinical practice against chronic C virus,especially in patients with advanced fibrosis. METHODS:Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1,treatment-na?ve(TN) or treatment-experienced(TE),who underwent triple therapy with the first generation NS3/4A protease inhibitors,boceprevir(BOC) and telaprevir(TVR),in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up.RESULTS:One thousand and fifty seven patients were included,405(38%) were treated with BOC and 652(62%) with TVR. Of this total,30%(n = 319) were TN and the remaining were TE:28%(n = 298) relapsers,12%(n = 123) partial responders(PR),25%(n = 260) null-responders(NR) and for 5%(n = 57) with prior response unknown. The rate of sustained virologic response(SVR) by intention-to-treatment(ITT) was greater in those treated with TVR(65%) than in those treated with BOC(52%)(P < 0.0001),whereas by modified intention-to-treatment(m ITT) no were found significant differences. By degree of fibrosis,56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients,both TN and TE. In the analysis by groups,the TN patients treated with TVR by ITT showed a higher SVR(P = 0.005). However,by m ITT there were no significant differences between BOC and TVR. In the multivariate analysis by m ITT,the significant SVR factors were relapsers,IL28 B CC and non-F4; the type of treatment(BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients,treated with BOC(46%) or with TVR(45%). 28% of the patients interrupted the treatment,mainly by non-viral response(51%):this outcome was more frequent in the TE than in the TN patients(57% vs 40%,P = 0.01). With respect to severe haematological disorders,neutropaenia was more likely to affect the patients treated with BOC(33% vs 20%,P ≤ 0.0001),and thrombocytopaenia and anaemia,the F4 patients(P = 0.000,P = 0.025,respectively). CONCLUSION:In a real clinical practice setting with a high proportion of patients with advanced fibrosis,effectiveness of first-generation PIs was high except for NR patients,with similar SVR rates being achieved by BOC and TVR.
基金Dr.T.P.Kingham was partially supported by the US National Cancer Institute MSKCC Core Grant number P30 CA00878 for this study.
文摘Background:The use of laparoscopic(LLR)and robotic liver resections(RLR)has been safely performed in many institutions for liver tumours.A large scale international multicenter study would provide stronger evidence and insight into application of these techniques for huge liver tumours≥10 cm.Methods:This was a retrospective review of 971 patients who underwent LLR and RLR for huge(≥10 cm)tumors at 42 international centers between 2002-2020.Results:One hundred RLR and 699 LLR which met study criteria were included.The comparison between the 2 approaches for patients with huge tumors were performed using 1:3 propensity-score matching(PSM)(73 vs.219).Before PSM,LLR was associated with significantly increased frequency of previous abdominal surgery,malignant pathology,liver cirrhosis and increased median blood.After PSM,RLR and LLR was associated with no significant difference in key perioperative outcomes including media operation time(242 vs.290 min,P=0.286),transfusion rate rate(19.2%vs.16.9%,P=0.652),median blood loss(200 vs.300 mL,P=0.694),open conversion rate(8.2%vs.11.0%,P=0.519),morbidity(28.8%vs.21.9%,P=0.221),major morbidity(4.1%vs.9.6%,P=0.152),mortality and postoperative length of stay(6 vs.6 days,P=0.435).Conclusions:RLR and LLR can be performed safely for selected patients with huge liver tumours with excellent outcomes.There was no significant difference in perioperative outcomes after RLR or LLR.
基金supported by grants from the Ministry of Economy and Competitiveness(FIS PI10/02529,FIS EC07/90762,FIS PI12/00760,FIS PI13/00666)the Ministry of Science and Technology(BIO2009-13903-C02-02)+4 种基金the Andalusian Government(P07-CVI-2781,PAIDI BIO-217,PI-0729-2010)Spanish Cell Therapy Network(TerCel)and CIBER-BBN are an initiative funded by the VI National R&D&I Plan 2008-2011(RD06/0010/0023,RD12/0019/0001)Advanced Therapies and Transplant General Direction(Health Ministry,Spain)(TRA-137),Iniciativa Ingenio 2010,Consolider Program,CIBER Actions,and financed by the Instituto de Salud Carlos Ⅲ(ISC-Ⅲ)with assistance from the European Regional Development FundWork in Munoz-Chapuli’s laboratory is supported by grants BFU2011-25304,BFU2012-35799,P11-CTS-7564,and PITN-GA-2011-289600in Raya’s laboratory by grants SAF2012-33526,ACI2010-1117,and ISC-Ⅲ(TerCel,RD12/0019/0019).
文摘The characterization and isolation of various stem cell populations, from embryonic to tissue-derived stem cells and induced pluripotent stem cells (iPSCs), have led to a rapid growth in the field of stem cell research and its potentially clinical application in the field of regenerative medicine and tissue repair. Stem cell therapy has recently progressed from the preclinical to the early clinical trial arena for a variety of diseases states, although further knowledge on action mechanisms, long-term safety issues, and standardization and characterization of the therapeutic cell products remains to be thoroughly elucidated. In this paper we summarize the current state of the art of basic and clinical research that were highlighted at the 2012 meeting of the Spanish Cell Therapy Network. This includes the current research involving in genomic and transcriptomic characterization of selected stem cell populations, studies of the role of resident and transplanted stem cells during tissue regeneration and their mechanism of action, improved new strategies of tissue engineering, transplantation of mesenchymal stem cells (MSCs) in different animal models of disease, disease correction by iPSCs, and preliminary results of cell therapy in human clinical trials.
文摘Cyclin-dependent kinases 4 and 6(CDK4/6)inhibitors demonstrated activity in terms of progression-free survival(PFS)in advanced dedifferentiated liposarcoma(DD-LPS),a sarcoma with CDK4 amplification.CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors.Preclinical investigators of this study found that CDK4 overexpression,while not of CDKN2A,was the most consistent predictive factor for palbociclib efficacy in sarcomas.Advanced adult-type soft-tissue sarcoma,excluding DD-LPS,or bone sarcoma patients,progressing after at least one systemic line,whose tumors overexpressed CDK4,but not CDKN2A at baseline biopsy,were accrued in this single-arm phase II trial(EudraCT number:2016-004039-19).With the main endpoint of a 6-month PFS rate,40%was considered promising in this population.Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles.A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening,archival material(141),and screening,baseline biopsy(95).There were 28(29%)with favorable mRNA profiles from 95 screened patients at baseline.From 23 enrolled patients,21 evaluable,the 6-month PFS rate was 29%(95%CI 9–48),and there were 6 patients out of 21 with a PFS longer than 6 months.The median PFS and overall survival were 4.2(95%CI 3.6–4.8)and 12(95%CI 8.7–15.4)months,respectively.Translational research showed a significant correlation between CDK4 mRNA and protein expression.Palbociclib was active in a variety of sarcoma subtypes,selected by CDK4/CDKN2A,and deserves further investigation in the sarcoma context.
文摘In the liver surgical oncology,a complete resection of the primary or metastatic liver tumors remains the main objective.If the tumor invades the hepatic vein or the inferior vena cava(IVC)a curative resection becomes challenging.However,recent advances in intraoperative hemodynamic management together with the refinement of the surgical technique acquired by complex liver surgery and transplantation have allowed to perform hepatic vein or vena cava resection for curation with low morbidity and mortality.
文摘Background and purpose Spain has been heavily affected by COVID-19.Reallocation of resources for managing the outbreak might have caused a disruption in stroke care.This study analyses the impact on stroke care of reorganising the healthcare system in response to the first COVID-19 outbreak peak in Spain and the strategies adopted by Spanish stroke units to deal with this impact.Materials and methods We obtained data from a structured survey sent to the responsible of stroke units across the country.We recorded the number of strokes,stroke code activations,intravenous thrombolysis treatments and mechanical thrombectomies during February and March 2019 and 2020.We also collected information on the impact on workflow metrics and on the availability of specialised neurological care and rehabilitation treatments,the characteristics of stroke care for patients with SARS-CoV-2 infection and the impact on human resources.We compared the activity data between 2019 and 2020 and the information on activity and impact on stroke care between regions classified according to the disease incidence rate.Results Fifty-seven(75%)of all stroke units in Spain responded to the survey.There was an overall reduction in admissions for all stroke types during the outbreak’s peak and in the number of stroke code activations and intravenous thrombolysis treatments,results that were independent of the COVID-19 incidence rate.Participants reported a delay in workflow metrics and a reduction of admissions to stroke units,outpatient clinics and rehabilitation therapies.Specific pathways and protocols for managing stroke patients with SARS-CoV-2 infection have been established.Conclusion The COVID-19 outbreak has jeopardised all phases of stroke care.As a consequence,some patients with stroke did not receive adequate treatment.
