Generation of colon cancer-derived tumor-infiltrating T cells (TILs) for adoptive cell therapy.

Adoptive cell therapy (ACT) using specific immune cells and stem cells has emerged as a promising treatment option that could complement traditional cancer therapies in the future. In particular, tumor-infiltrating lymphocytes (TILs) have been shown to be effective against solid tumors in various clinical trials. Despite the enormous disease burden and large number of premature deaths caused by colorectal cancer (CRC), studies on TILs isolated from tumor tissue of patients with CRC are still rare. To date, studies on ACT often lack controlled and comparable expansion processes as well as selected ACT-relevant T-cell populations. We describe a procedure for generating patient-specific TILs, which are prerequisites for clinical trials of ACT in CRC. The manufacturing and characteristics of these TILs differ in important modalities from TILs commonly used for this therapeutic approach. Tumor tissue samples were obtained from 12 patients undergoing surgery for primary CRC, predominantly with low microsatellite instability (pMMR-MSI-L). Tumors in the resected specimens were examined pathologically, and an approved volume of tumor tissue was transferred to a disposable perfusion bioreactor. Tissue samples were subjected to an automatically controlled and highly reproducible cultivation process in a GMP-conform, closed perfusion bioreactor system using starting medium containing interleukin-2 and interleukin-12. Outgrowth of TIL from tissue samples was initiated by short-term supplementation with a specific activation cocktail. During subsequent expansion, TILs were grown in interleukin-2-enriched medium. Expansion of TILs in a low-scaled, two-phase process in the Zellwerk ZRP bioreactor under hyperoxic conditions resulted in a number of approximately 2 × 109 cells. The expanded TILs consisted mainly (73%) of the ACT-relevant CD3+/CD8+ effector memory phenotype (CD45RO+/CCR7-). TILs harvested under these conditions exhibited high functional potential, which was confirmed upon nonspecific stimulation (interferon-γ, tumor necrosis factor-α cytokine assay).

Tumor-infiltrating lymphocytes mediate complete and durable remission in a patient with NY-ESO-1 expressing prostate cancer.

Adoptive transfer of autologous tumor-specific lymphocytes represents a viable treatment method for patients with advanced malignancies. Here, we report a patient's case with metastatic hormone-refractory New York esophageal squamous cell carcinoma 1 (NY-ESO-1) expressing prostate cancer treated with in vitro expanded tumor-infiltrating lymphocytes (TILs) in conjunction with IL-2 and immune-checkpoint blockade. Complete and durable tumor remission was observed after three TIL infusions consisting of 1.4×109, 2.0×109, and 8.0×109 T cells, respectively, lasting now for more than 3.5 years. Immunological correlates to the clinical development were the decrease of tumor-driven NY-ESO-1 serum antibody and the drop of prostate-specific antigen to <0.01 µg/L. TILs were reactive against cancer-testis antigen NY-ESO-1, individual tumor mutational proteins (eg, PRPF8, TRPS1), and the androgen receptor splice variant 12.

Procedural Success Rates and Mortality in Elderly Patients With Percutaneous Coronary Intervention for Cardiogenic Shock.

OBJECTIVES: The aim of this study was to determine the impact of age on procedural and clinical outcomes in patients with cardiogenic shock (CS). BACKGROUND: The use of early revascularization therapy with percutaneous coronary intervention (PCI) has been shown to improve outcome in patients with acute myocardial infarction (AMI) complicated by CS. METHODS: Data from consecutive patients with AMI and CS treated with PCI enrolled into the prospective ALKK (Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte) PCI registry were centrally collected and analyzed. Patients were divided into 4 groups according to their age (<65, 65 to 74, 75 to 84, and >85 years). Patients' characteristics, procedural features, antithrombotic therapies, and in-hospital complications were compared among the 4 groups. RESULTS: Between 2010 and 2015, a total of 2,323 consecutive patients with AMI and CS were treated by PCI in 51 hospitals. TIMI (Thrombolysis In Myocardial Infarction) flow grade 3 patency after PCI decreased with increasing age from 84% to 78%, while in-hospital mortality increased from 32% to 56%. Bleeding rates were low (2.0% to 2.3%) and not different among age groups. In the multivariate analysis, higher age, TIMI flow grade <3 after PCI, 3-vessel disease, and left main PCI were independent predictors of mortality. CONCLUSIONS: PCI in patients with AMI and CS is associated with a high procedural success rate and a low bleeding rate, even in very elderly patients, while mortality increases with increasing age. Because mortality in elderly patients with CS without revascularization therapy is very high, it seems justified to perform PCI in selected patients to reduce mortality.

Mass Production of Highly Active NK Cells for Cancer Immunotherapy in a GMP Conform Perfusion Bioreactor.

NK cells have emerged as promising candidates for cancer immunotherapy, especially due to their ability to fight circulating tumor cells thereby preventing metastases formation. Hence several studies have been performed to generate and expand highly cytotoxic NK cells ex vivo, e.g., by using specific cytokines to upregulate both their proliferation and surface expression of distinct activating receptors. Apart from an enhanced activity, application of NK cells as immunotherapeutic agent further requires sufficient cell numbers and a high purity. All these parameters depend on a variety of different factors including the starting material, additives like cytokines as well as the culture system. Here we analyzed PBMC-derived NK cells of five anonymized healthy donors expanded under specific conditions in an innovative perfusion bioreactor system with respect to their phenotype, IFNγ production, and cytotoxicity in vitro. Important features of the meander type bioreactors used here are a directed laminar flow of medium and control of relevant process parameters. Cells are cultivated under "steady state" conditions in perfusion mode. Our data demonstrate that expansion of CD3+ T cell depleted PBMCs in our standardized system generates massive amounts of highly pure (>85%) and potent anti-cancer active NK cells. These cells express a variety of important receptors driving NK cell recruitment, adhesion as well as activation. More specifically, they express the chemokine receptors CXCR3, CXCR4, and CCR7, the adhesion molecules L-selectin, LFA-1, and VLA-4, the activating receptors NKp30, NKp44, NKp46, NKG2D, DNAM1, and CD16 as well as the death ligands TRAIL and Fas-L. Moreover, the generated NK cells show a strong IFNγ expression upon cultivation with K562 tumor cells and demonstrate a high cytotoxicity toward leukemic as well as solid tumor cell lines in vitro. Altogether, these characteristics promise a high clinical potency of thus produced NK cells awaiting further evaluation.

Recommendations for extracorporeal cardiopulmonary resuscitation (eCPR): consensus statement of DGIIN, DGK, DGTHG, DGfK, DGNI, DGAI, DIVI and GRC.

Extracorporeal cardiopulmonary resuscitation (eCPR) may be considered as a rescue attempt for highly selected patients with refractory cardiac arrest and potentially reversible aetiology. Currently, there are no randomised, controlled studies on eCPR. Thus, prospective validated predictors of benefit and outcome are lacking. Currently, selection criteria and procedure techniques differ across hospitals and standardised algorithms are lacking. Based on expert opinion, the present consensus statement provides a first standardised treatment algorithm for eCPR.

Sex Differences in Percutaneous Coronary Intervention-Insights From the Coronary Angiography and PCI Registry of the German Society of Cardiology.

BACKGROUND: Several studies have suggested sex-related differences in diagnostic and invasive therapeutic coronary procedures. METHODS AND RESULTS: Data from consecutive patients who were enrolled in the Coronary Angiography and PCI Registry of the German Society of Cardiology were analyzed. We aimed to compare sex-related differences in in-hospital outcomes of patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease, non-ST elevation acute coronary syndromes, ST elevation myocardial infarction, and cardiogenic shock. From 2007 until the end of 2009 data from 185 312 PCIs were prospectively registered: 27.9% of the PCIs were performed in women. Primary PCI success rate was identical between the sexes (94%). There were no sex-related differences in hospital mortality among patients undergoing PCI for stable coronary artery disease, non-ST elevation acute coronary syndromes, or cardiogenic shock except among ST elevation myocardial infarction patients. Compared to men, women undergoing primary PCI for ST elevation myocardial infarction have a higher risk of in-hospital death, age-adjusted odds ratio (1.19, 95% CI 1.06-1.33), and risk of ischemic cardiac and cerebrovascular events (death, myocardial infarction, transient ischemic attack/stroke), (age-adjusted odds ratio 1.19, 95% CI 1.16-1.29). Furthermore, access-related complications were twice as high in women, irrespective of the indication. CONCLUSIONS: Despite identical technical success rates of PCI between the 2 sexes, women with PCI for ST elevation myocardial infarction have a 20% higher age-adjusted risk of death and of ischemic cardiac and cerebrovascular events. Further research is needed to determine the reasons for these differences.

Effect of GPIIb/IIIa inhibition with eptifibatide or tirofiban on the expression of cellular adhesion molecules on monocytes.

AIM: The aim of the present study was to investigate the effect of GPIIb/IIIa inhibition with eptifibatide and tirofiban on the expression of cellular adhesion molecules on monocytes at different temperatures. MATERIALS AND METHODS: Circulation of blood from six volunteers was performed in an extracorporal circulation model at 36°C and 18°C for 30 min. The blood of each donor was prepared either with addition of eptifibatide or tirofiban, or was left untreated as control. CD54 and CD162 on monocytes was measured using flow cytometry. RESULTS: Expression of CD11b was lower at 18°C compared to 36°C by 51% in the eptifibatide group (p=0.0043), by 29% in the tirofiban group (p=0.095) and by 34% in the control group (p=0.038). Expression of CD54 was not significantly different at 18°C compared to 36°C, neither with eptifibatide (p=0.29) nor tirofiban (p=0.48) nor in the control group (p=0.26). Expression of CD162 was lower at 18°C compared to 36°C by 40% using eptifibatide (p=0.0010), by 94% using tirofiban (p=0.0095) and by 34% in the control group (p=0.019). At 36°C and 18°C, no significant differences were found regarding the expression of CD11b, CD54 and CD162 between the eptifibatide-treated group, the tirofiban-treated group and the control group. CONCLUSION: GPIIb/IIIa inhibition with eptifibatide or tirofiban seems to have no effect on the expression of CD11b, CD54 and CD162 on monocytes during normothermia or hypothermia. Our results show that the beneficial effect induced by hypothermia on the extracorporal circulation-associated alteration of leukocyte function, with decreased expression of CD11b and CD162, seems not to be affected by additional treatment with eptifibatide or tirofiban.

Expression of CD11b (MAC-1) and CD162 (PSGL-1) on monocytes is decreased under conditions of deep hypothermic circulatory arrest.

Deep hypothermic circulatory arrest (DHCA) is a common technique used to protect vital organs during surgical interventions on the thoracic aorta or during surgery for complex congenital heart disease. Activated leukocytes are key mediators of inflammatory responses during ischemia. Intercellular crosstalk between leukocytes, platelets and endothelial cells is mediated by cell adhesion molecules. These molecules trigger complex cell-cell interaction mechanisms and initiate the release of proinflammatory molecules. One parameter that is known to have a significant impact on inflammatory cell activation and the production of proinflammatory markers is temperature. However, to the best of our knowledge, no data have yet been published on the effect of hypothermia on leukocyte surface markers during DHCA. Thus, the aim of the present study was to investigate the effect of hypothermia on the expression of cell adhesion molecules on monocytes under DHCA conditions in vitro. Blood samples collected from 11 healthy volunteers were incubated in a well-established model simulating circulatory arrest at 36°C and 18°C for 30 min. The expression of cluster of differentiation (CD) molecule 11B (CD11b), CD54 and CD162 on monocytes was measured as the mean fluorescence intensity (MFI) using flow cytometry. The expression level of CD11b on monocytes was significantly decreased following the incubation of the blood samples at 18°C compared with the level in blood samples incubated at 36°C (P<0.001). After 30 min of blood stasis in the circulatory arrest model, the expression level of CD162 on monocytes was significantly lower in the blood samples incubated at 18°C than in those incubated at 36°C (P<0.001). No association was identified between temperature and the surface expression of CD54 on monocytes following 30 min of stasis. These findings demonstrate that deep hypothermia decreases the expression of CD11b and CD162 on monocytes in an experimental setup simulating the conditions of DHCA. This may be the result of the inhibition of leukocyte-endothelial and leukocyte-platelet interactions, which may be a beneficial aspect of deep hypothermia that affects the inflammatory response and tissue damage during DHCA.

[An overview: new direct oral anticoagulants (DOAC)]. / Ein Überblick.

For stroke prevention in patients with atrial fibrillation and other indications new oral anticoagulants have been developed. These drugs are direct anticoagulants in contrast to the indirectly acting vitamin-K antagonists, which are used for decades as the only available drugs. Most clinical experience exists for the thrombin inhibitor dabigatran and the factor X inhibitorrivaroxaban. However, to transfer the benefit from the large scale studies to the real world conditions, physicians have to get clinical experience in using the new drugs. Especially drug interactions, impaired renal function and periinterventional bridging need special attention to ensure transfer of the new drugs benefits to daily life treatment.

Hypothermia inhibits expression of CD11b (MAC-1) and CD162 (PSGL-1) on monocytes during extracorporeal circulation.

AIM: The aim of the present study was to investigate the effect of different hypothermic temperatures on the expression of cellular adhesion molecules on leukocytes. MATERIALS AND METHODS: Circulation of blood from six volunteers was performed in an extracorporeal circulation model at 36°C, 28°C and 18°C for 30 minutes. Expression of CD11b, CD54 and CD162 on monocytes was measured using flow cytometry. RESULTS: Expression of CD11b significantly decreased at 18°C and at 28°C compared to 36°C. A significant reduction of CD162 expression was found at 18°C compared to 28°C and 36°C and at 28°C compared to 36°C. No association was found between temperature and expression of CD54. CONCLUSION: Expression of CD11b and CD162 on monocytes has a temperature-dependent regulation, with decreased expression during hypothermia, which may result in an inhibition of leukocyte-endothelial and leukocyte-platelet interaction. This beneficial effect may influence the extracorporeal circulation-related inflammatory response and tissue damage.

Investigation of platelet adhesiveness in patients with coronary artery disease and acute myocardial infarction using the platelet adhesion assay (PADA).

BACKGROUND: Increased platelet reactivity may contribute to the development of coronary artery disease and myocardial infarction. The aim of the present study was to assess platelet adhesiveness in different stages of coronary artery disease using the platelet adhesion assay (PADA). In addition, the acute effect of coronary angiography and stent implantation on platelet adhesiveness was examined. METHODS: 85 patients with stable coronary artery disease (SAP - stable angina pectoris) and 19 patients with acute myocardial infarction (AMI) were enrolled in the study. 35 volunteers served as controls. Blood sampling in SAP and AMI patients was done before coronary angiography to measure the adhesion index (AI) using the PADA. In 33 patients additional blood was drawn at the end of coronary angiography. In 6 patients blood samples were drawn also after stent implantation. RESULTS: In blood samples from patients with an AMI the AI was significantly higher than in blood samples from the SAP group (p < 0.01) and the control group (p < 0.01). Coronary angiography and stent implantation did not result in significant acute changes in mean AI however results show an interindividual variability in initial values as well as in AI changes during procedures. CONCLUSIONS: This is the first study to show that PADA, a quick and simple laboratory method for the quantitative determination of platelet adhesiveness, is able to detect platelet hyper-adhesiveness in patients with AMI.

Thrombogenicity of sirolimus-eluting stents and bare metal stents: evaluation in the early phase after stent implantation.

BACKGROUND: Thrombogenicitiy of drug-eluting stents is a matter of controversial debate. The aim of this study was to evaluate the thrombogenicity of sirolimus-eluting stents (SES) compared to bare metal stents (BMS) in a standardised in vitro model. MATERIALS AND METHODS: Nine SES and nine BMS were implanted in tubing loops and nine loops without stent served as controls. Initially and after 90 minutes of blood circulation in a modified chandler loop model, thrombin-antithrombin III complex (TAT), PMN-elastase, factor XIIa, SC5b-9, sP-selectin and platelet count were measured. Expression of CD62P, CD45/41 and PAC-1 on platelets were determined by flow cytometry. RESULTS: After 90 minutes, platelet count decreased significantly in the loops with BMS and SES (p<0.05). Levels of TAT, PMN-elastase and SC5b-9 were significantly elevated after 90 minutes in all loops (p<0.05). sP-selectin significantly increased in the loops with BMS and SES after 90 minutes. No significant changes occurred in any flow cytometric data. Platelet count, sP-selectin, TAT, PMN-elastase, SC5b-9, CD62P, CD41/CD45 and PAC-1 showed no significant difference between BMS and SES. CONCLUSION: These data provide evidence that there is no difference in thrombogenicity of BMS and SES in the in vitro model.

Effect of atorvastatin on haemostasis, fibrinolysis and inflammation in normocholesterolaemic patients with coronary artery disease: a post hoc analysis of data from a prospective, randomized, double-blind study.

BACKGROUND: Treatment with HMG-CoA reductase inhibitors (statins) reduces the morbidity and mortality of coronary artery disease (CAD). In addition to their lipid-lowering actions, pleiotropic effects of statins have been demonstrated. OBJECTIVE: The aim of the present study was to assess if atorvastatin therapy has an impact on haemostasis, fibrinolysis and inflammation in normocholesterolaemic patients with CAD. METHODS: Fifty-four patients with CAD who had received atorvastatin treatment for at least 8 weeks (mean dosage 30 mg/day) and 54 patients with CAD who had not received atorvastatin therapy were selected from a larger prospective, randomized, double-blind study for inclusion in this post hoc analysis. Patients were matched by their total cholesterol levels. All patients were normocholesterolaemic. RESULTS: In the atorvastatin-treated patients significantly lower plasma levels of thrombin-antithrombin complexes (p < 0.05), plasminogen activator inhibitor-1 activity (PAI-1) [p < 0.05], soluble vascular cell adhesion molecule-1 (p < 0.05), soluble platelet selectin (p < 0.05) and high-sensitivity C-reactive protein (p < 0.05) were measured compared with patients not on atorvastatin therapy. Additionally, a strong trend towards lower soluble intercellular adhesion molecule-1 plasma levels was detected in patients treated with atorvastatin. No differences were found in tissue-type plasminogen activator antigen, plasmin-plasmin inhibitor complexes, fibrinogen, D-dimer and activated factor XII values. CONCLUSION: Atorvastatin appears to have an effect on coagulation activation, fibrinolysis and inflammation in patients with CAD. Reduction in PAI-1 and reduced thrombin formation may have an impact on cardiovascular morbidity and mortality in patients with CAD.

Effect of atorvastatin on cellular adhesion molecules on leukocytes in patients with normocholesterolemic coronary artery disease.

BACKGROUND: Expression of cellular adhesion molecules on leukocytes plays a key role in coronary artery disease (CAD). The aim of the present study was to assess whether atorvastatin therapy has an impact on the expression of cellular adhesion molecules on leukocytes in patients with normocholesterolemic CAD. PATIENTS AND METHODS: In 54 patients with CAD and atorvastatin treatment and 54 CAD patients without atorvastatin therapy, expression of CD40L, CD11a, CD11b, CD54, CD62L and CD41 on leukocytes was measured using flow cytometry. All patients were normocholesterolemic. RESULTS: Atorvastatin treatment led to a significantly lower expression of CD40L, CD11b and CD54 on monocytes (p<0.05) and neutrophils (p<0.05). Expression of CD11a was significantly lower on monocytes (p<0.05) in atorvastatin-treated patients. CONCLUSION: The present results indicate that atorvastatin apparently improves chronic inflammation and may have a beneficial effect on hemostasis by reducing the expression of cellular adhesion molecules on leukocytes.

Abciximab combined with half-dose reteplase has beneficial effects on inflammatory myocardial response in patients with myocardial infarction.

In patients with ST-segment elevation myocardial infarction (STEMI), myocardial reperfusion is associated with an inflammatory response leading to adverse effects on further myocardial damage. Therefore, we investigated the effects of the thrombolytic regimen with half-dose reteplase (r-PA) combined with abciximab on different cytokines involved in the local and systemic inflammatory scenario in STEMI patients. Thirty-eight STEMI patients were enrolled in this study. We investigated the effects of the regimen with half-dose r-PA plus abciximab versus full-dose r-PA on interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), MCP-1 and tumor necrosis factor-alpha (TNF-alpha) up to 48 h after the start of therapy. The full-dose r-PA group had a significant IL-6 increase after 48 h compared with the combination group. Furthermore, the full-dose r-PA group showed a marked increase of IL-10 (up to 3 h after) compared with a 41% IL-10 decrease in the combination group. MCP-1 decreased significantly after 3 h in the combination group compared with patients on r-PA therapy only. The combination group showed a nonsignificant increase in IL-8 within the first 6 h. There were no differences in TNF-alpha levels between the two infarct groups. In vivo, the investigated combined thrombolytic regimen consisting of half-dose r-PA plus abciximab causes less of an IL-6 increase and marked decreases in IL-10 and MCP-1 in STEMI patients compared with the pure r-PA thrombolytic regimen. This observation suggests that besides the known beneficial effects on systemic coagulation and leukocyte-platelet aggregates, this regimen may exert a favorable influence on myocardial tissue damage and thus on cardiac repair following myocardial infarction.

Effect of clopidogrel on adhesion molecules, hemostasis, and fibrinolysis in coronary heart disease.

BACKGROUND: The interaction among inflammation, Hemostasis, and fibrinolysis plays a major role in the genesis of coronary artery disease (CAD). The aim of the study was to compare the effect of clopidogrel plus aspirin versus aspirin alone on cellular adhesion molecules on leukocytes, soluble adhesion molecules, and molecular markers of coagulation and fibrinolysis in patients with CAD. METHODS: In this randomized, placebo-controlled, and double-blind study, 42 patients with chronic angina pectoris were included. All patients were treated with aspirin (ASA). Twenty-three patients received clopidogrel additionally (75 mg/day with a 300-mg loading dose) for 14 days. Nineteen patients received placebo additionally. Soluble adhesion molecules (sICAM-1, sVCAM-1, sP-selectin), surface expression of CD54, CD11a, CD11b, CD40, CD40L, CD41, CD42b, and CD62L on lymphocytes, monocytes, and neutrophils, and markers of hemostasis and fibrinolysis (TAT, PAP, D-dimers) were measured. RESULTS: In the ASA + clopidogrel group, no change in surface expression of cellular adhesion molecules on leukocytes and on plasma levels of sICAM-1, sVCAM-1, sP-selectin, TAT, PAP, and D-dimers was detectable. CONCLUSIONS: Clopidogrel plus aspirin for 2 weeks did not result in a detectable benefit versus sole aspirin therapy regarding cellular adhesion molecules on leukocytes, plasma markers of coagulation, fibrinolysis, and soluble adhesion molecules in patients with CAD.

[Optimal platelet inhibition after coronary stent implantation. Current status]. / Optimale Thrombozytenaggregationshemmung nach koronarer Stentimplantation: Aktueller Stand.

Percutaneous coronary intervention (PTCA, PCI) is the most frequently used therapy for the treatment of stenoses or occlusions of coronary arteries. In Germany, six PCIs are performed for every coronary bypass surgery. Today, stents are implanted in over 80% of PCIs to improve the acute and long-term results. The most feared complication after stent implantation is the acutely occurring stent thrombosis, which usually leads to a myocardial infarction with its relatively high mortality. The introduction of platelet inhibition (acetylsalicylic acid [ASA] and ticlopidine/clopidogrel) decreased the rate of early ( 30 days to 1 year) or very late (> 1 year) stent thromboses after BMS, but they do occur. Whereas a dual platelet inhibition of 4 weeks is sufficient after BMS, it must be performed longer after DES due to its prolonged period of endothelialization. In the randomized DES versus BMS studies, the rates of late and very late stent thromboses were increased with DES in the range of approximately 1 per thousand annually - but without affecting the mortality. DES may prevent myocardial infarctions by reducing restenoses, thus offsetting the possibly negative effects of late stent thrombosis. In patients with more extensive disease, previously sent to bypass surgery, the rate of late and very late stent thromboses is in the range of 0.6% per year. Since there is no control group from major randomized studies for these patients, more data have to be awaited.The optimal duration of dual platelet inhibition after DES is unknown, since no prospective, randomized trials have addressed this question. Based on the presently available data, clopidogrel must be given in addition to ASA for at least 6 months. Depending on the individual risk of stent thrombosis and the individual risk of bleeding, clopidogrel can be administered for 1 year or longer. Although a diminished effect of ASA and/or clopidogrel is known to be present in some patients, laboratory testing of platelet aggregation cannot be recommended for clinical decision- making at the present time due to missing standards and lack of pivotal studies. For clopidogrel, an increased platelet inhibition has been described with double dose (75 mg bid), but the clinical relevance is unknown. Whether new thienopyridine derivatives, like prasugrel, will also be superior to clopidogrel under "everyday" conditions has still to be shown. In patients with proven indication for chronic anticoagulation, the use of DES should be restricted or avoided. If a DES was nevertheless implanted, triple therapy (coumadin, ASA, and clopidogrel) is recommended--with an INR (International Normalized Ratio) target of 2.0, possibly adding a proton pump inhibitor. In case of nondeferrable surgery, dual platelet inhibition should be continued, if possible (like dental extractions), or perioperatively converted to a small-molecule glycoprotein IIb/IIIa inhibitor--under in-hospital survey. Further developments of next-generation DES with different drugs, modified release kinetics, specifically abluminal drug release or bioabsorbable polymers or absorbable stents are necessary, in order to reduce the duration of dual platelet inhibition to the range of BMS--but maintaining the well-established antiproliferative effects of DES.