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The granted European patent EP 2 561 890 describes a procedure for an immunological treatment of cancer. It is based on the principles of the HLA-supported communication of implantation and pregnancy. These principles ensure that the embryo is not rejected by the mother. In pregnancy, the placenta, more specifically the trophoblast, creates an "interface" between the embryo/fetus and the maternal immune system. Trophoblasts do not express the "original" HLA identification of the embryo/fetus (HLA-A to -DQ), but instead show the non-classical HLA groups E, F, and G. During interaction with specific receptors of NK cells (e.g., killer-immunoglobulin-like receptors (KIR)) and lymphocytes (lymphocyte-immunoglobulin-like receptors (LIL-R)), the non-classical HLA groups inhibit these immunocompetent cells outside pregnancy. However, tumors are known to be able to express these non-classical HLA groups and thus make use of an immuno-communication as in pregnancies. If this occurs, the prognosis usually worsens. This patent describes, in a first step, the profiling of the non-classical HLA groups in primary tumor tissue as well as metastases and recurrent tumors. The second step comprises tailored antibody therapies, which is the subject of this patent. In this review, we analyze the underlying mechanisms and describe the currently known differences between HLA-supported communication of implantation and that of tumors.

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The basis for primary and secondary prevention of stroke (and also TIA) are both a healthy lifestyle with a healthy diet, non smoking, weight reduction and regular exercise, and consistent treatment of arterial hypertension with a target of < 140 /90 mmHg. The choice of the antihypertensive is depending on concomitant diseases, more important than the class of antihypertensive is treatment to target. Reduction of cholesterol with statins in primary prevention is dependant on total cardiovascular risk, in secondary prevention statins are integral part of modern treatment in non cardioembolic stroke. Atrial fibrillation is one of the major causes of stroke and should be treated with anticoagulation depending on the CHA2DS2-VASc score. Platelet inhibition is mandatory lifelong in all non cardioembolic strokes, in primary prevention only for patients with high total cardiovascular risk. Treatment of asymptomatic carotid artery stenosis should be determined on an individual basis. Symptomatic carotid artery stenosis should be treated immediately after the index stroke.

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INTRODUCTION: There are few clinical trials that provide evidence to support the hypothesis that combined therapies offer a favorable risk-benefit ratio in the reduction of cardiovascular mortality and morbidity. Combined therapies containing an angiotensin-converting enzyme inhibitor (ACEI) with a calcium channel blocker (CCB) is one of the recommended combinations in the reappraisal of the European Society of Hypertension. AREAS COVERED: The authors have performed a systematic review of the available clinical evidence on the use of combined therapies containing an ACEI with a CCB versus other combinations in the management of arterial hypertension (HT) and in the reduction of cardiovascular morbidity/mortality, according to recommendations of The Cochrane Handbook for Systematic Reviews of Interventions. They identified 122 potentially relevant studies. Of these, 38 included combined therapies in one or both treatment arms. Overall, a total of 12 publications were retrieved from the search and provided data on the effects of the combined therapy with an ACEI and a CCB on cardiovascular mortality/morbidity in patients with HT. Clinical evidence corresponds to three double-blind clinical trials: ASCOT-BPLA, ACCOMPLISH and Syst-EUR. EXPERT OPINION: The analysis demonstrates the superiority of the combined therapy with ACEI/CCB not only in the overall population included in the studies but also in subsets of patients with a high cardiovascular risk such as diabetes and chronic kidney disease.

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BACKGROUND: A fixed-dose combination (FDC) of enalapril and lercanidipine has been shown to be effective and safe in reducing blood pressure in randomized clinical trials. This study aims to determine effectiveness and safety in daily practice. METHODS: This was a prospective, open-label, uncontrolled multicenter study, with a 3-month follow-up at general practitioners and internists. Patients were treated with an FDC of 20 mg enalapril maleate and 10 mg lercanidipine hydrochloride, and blood pressure was determined in the office (OBPM) and by discretionary self- (SBPM) and ambulatory- (ABPM) measurements. RESULTS: Out of 622 patients (mean age 61.3 ± 13.3 years, 54.2% male): blood pressure was reduced by -29.2/-14.2 mmHg (OBPM) from baseline (164.4/95.2 mmHg). Pulse pressure was reduced by -15.0 ± 16.4 mmHg. Prevalence of microalbuminuria was reduced from 14.6% at baseline to 6.5% (p < 0.001). SBPM data were available for 71% of patients and ABPM for 12%. In the latter patients, blood pressure variability index was significantly reduced compared with baseline over 24 h (14.2 ± 4.2 vs 16.3 ± 4.0; p < 0.001) and with nighttime ABPM (13.7 ± 4.9 vs 15.2 ± 4.4; p = 0.022). Treatment was associated with a low incidence of adverse events (3.4%). CONCLUSIONS: The FDC of 20 mg enalapril-maleate and 10 mg lercanidipine-hydrochloride seems to be effective and well tolerated in clinical practice. It improved vascular surrogate end points, including pulse pressure, blood pressure variability and microalbuminuria.

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OBJECTIVE: Most patients with hypertension require antihypertensive combination therapy to achieve BP control. This study investigated the safety and efficacy of the direct renin inhibitor aliskiren combined with the calcium channel blocker amlodipine. METHODS: Overall, 556 patients with hypertension (msDBP > or =95-<110 mmHg) received open-label aliskiren/amlodipine 150/5 mg for 2 weeks, followed by forced titration to aliskiren/amlodipine 300/10 mg for 52 weeks. Add-on hydrochlorothiazide (HCT) was permitted from week 10 to achieve BP control (<140/90 mmHg). The primary objective of the study was to evaluate the long-term safety and tolerability of aliskiren/amlodipine combination therapy; the BP-lowering efficacy of the combination was also assessed (week 54 endpoint; last observation carried forward). TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00402103. RESULTS: In total, 452 patients completed 54 weeks' treatment with aliskiren/amlodipine 300/10 mg, with or without add-on HCT. The most frequently reported adverse events (AEs) were peripheral edema, upper respiratory tract infection, headache and bronchitis. Peripheral edema (the most common AE), occurred in 22.7% of treated patients, and was generally mild or moderate in intensity and transient in nature. Few patients exhibited laboratory abnormalities. Aliskiren/amlodipine combination therapy provided a mean BP reduction from baseline to week 54 of 24.2/15.5 mmHg; 74.3% of patients achieved BP control. In the subgroup of patients with stage 2 hypertension (baseline msSBP > or =160 mmHg and/or msDBP > or =100 mmHg), the mean BP reduction at week 54 was 29.1/17.1 mmHg, and 67.0% of patients achieved BP control. CONCLUSION: In this open-label study, aliskiren/amlodipine 300/10 mg combination therapy, with or without add-on HCT, effectively reduced BP, particularly in patients with stage 2 hypertension. The most common AE was peripheral edema, consistent with the known AE profile of high-dose (10 mg) amlodipine. Further studies comparing the aliskiren/amlodipine combination with the component monotherapies and other antihypertensive combinations are warranted.

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BACKGROUND: The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment. METHODS: A total of 1008 participants with high-normal office blood pressure were randomized to ramipril treatment group (n = 505) and a control group (n = 503). The patients were followed up for 3 years. Primary endpoint was to prevent or delay the progression to manifest hypertension. Secondary endpoints were reduction in the incidence of cerebrovascular and cardiovascular events, as well as the development of hypertension as defined by ambulatory blood pressure monitoring. FINDINGS: One hundred and fifty-five patients (30.7%) in the ramipril group, and 216 (42.9%) in the control group reached the primary endpoint (relative risk reduction 34.4%, P = 0.0001). Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure. The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups. Cough was more frequent in the ramipril group (4.8 vs. 0.4%). INTERPRETATION: There is now good clinical evidence that patients with high-normal blood pressure (prehypertension) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure. Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis. Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated, and significantly reduced the risk of progression to manifest hypertension.

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BACKGROUND: Tight blood pressure (BP) control is required to reduce cardiovascular morbidity and mortality. OBJECTIVE: To evaluate the efficacy and tolerability of the first line combination perindopril/indapamide in hypertension in daily practice. DESIGN AND METHODS: In this prospective, open-label, observational trial, 1892 general practitioners in Germany recruited patients with hypertension (n = 8023; mean age 59.6 years, 48.1% males, body mass index 27.6 kg/m2, systolic BP >or= 140 mmHg and/or diastolic BP >or= 90 mmHg) between October 2002 and December 2004. Patients received perindopril 2 mg/indapamide 0.625 mg for 12 weeks. BP measured in the general practice setting, safety, and tolerability were evaluated after 4 and 12 weeks. RESULTS: At baseline, most patients had moderate to severe hypertension (78%); initial BP was 164.6/95.8 mmHg. At inclusion, 38% of the patients were newly diagnosed hypertensives (mean BP 166.1/97.2 mmHg) and 58% of patients had uncontrolled BP despite preexisting antihypertensive treatment (163.5/94.9 mmHg). Previous treatment consisted of beta-blockers (49.5%), ACE inhibitors (36.4%), calcium-antagonists (29.3%), diuretics (28.8%), AT-I receptor antagonists (7.1%), and other treatments (8.1%). In the entire study cohort, treatment with perindopril/indapamide significantly decreased systolic BP (27.9 mmHg), diastolic BP (13.7 mmHg), and pulse pressure (14.2 mmHg), compared with baseline (p < 0.0001); 96% of patients responded to treatment and in 50% of patients BP was normalized (< 140/90 mmHg). Treatment dose was doubled in 9.5% of patients. Similar results were found in various subgroup analyses (newly diagnosed patients, the elderly, and patients with isolated systolic hypertension, additional cardiovascular risk factors, associated diseases, or target organ damage). The most frequent adverse events (< 1% of patients) were dry cough and nausea. CONCLUSIONS: The open-label, observational study PRIMUS, extends the existing evidence that the first line combination treatment of hypertension with perindopril/indapamide is effective, safe, and well tolerated in a representative cross-section of patients with newly diagnosed or pretreated but uncontrolled hypertension in daily practice.

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Principal results of the Study on COgnition and Prognosis in the Elderly (SCOPE) were published in 2003. Blood pressure reduction was pronounced in both the candesartan and control groups, with little difference. With candesartan-based treatment, compared with control, the relative risk of non-fatal stroke was 0.72 (P = 0.04) and of major cardiovascular events 0.89 (P = 0.19). There were no significant differences in cognitive outcomes. We have reviewed recent subgroup analyses in SCOPE. Cardiovascular endpoints were analysed in patients who did not receive add-on treatment after random allocation to groups (post hoc) and in patients with certain characteristics at baseline, such as age, sex, diabetes, isolated systolic hypertension, or a history of stroke. Cognitive endpoints were analysed in patients with baseline Mini Mental State Examination (MMSE) score 24-28, and in those examined with more extensive investigations than the MMSE. In patients without add-on treatment, there were significant risk reductions in the candesartan group in major cardiovascular events [relative risk (RR) 0.68, 95% confidence interval (CI) 0.51 to 0.92] and mortality (RR 0.73, 95% CI 0.57 to 0.95). In other subgroups, the relative risks for major cardiovascular events and stroke were generally consistent with those in the entire study population. However, risk reductions in the candesartan group were particularly marked in patients with a history of stroke. In patients with MMSE score 24-28 at baseline, the score declined significantly less in the candesartan group (between-group difference 0.49, 95% CI 0.02 to 0.97). Cardiovascular outcome benefit of candesartan-based treatment was most evident in patients without add-on treatment and in those with a history of stroke. Results in other subgroups were generally consistent with those in the entire SCOPE study population. In patients with slightly low cognitive function at baseline, the MMSE score declined less in the candesartan group.

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BACKGROUND: We examined whether cognitive function at baseline affected cognitive and cardiovascular outcomes in the Study on COgnition and Prognosis in the Elderly (SCOPE), a blood pressure (BP)-lowering intervention trial. METHODS: SCOPE included 4937 patients, aged 70 to 89 years, with mild-to-moderate hypertension and Mini Mental State Examination (MMSE) score > or =24. Double-blind treatment was initiated with candesartan or placebo. Open-label therapy was added as needed to control BP, both in the candesartan (49%) and control (66%) groups. Mean follow-up was 3.7 years. Low cognitive function (LCF) at baseline was defined as MMSE score 24 to 28 (N = 2070), and high cognitive function (HCF) as MMSE score 29 to 30 (N = 2867). RESULTS: Mean BP reductions were approximately 20/10 mm Hg both in LCF and HCF patients, with greater reductions in the candesartan group than in the control group. The incidence of dementia was higher in LCF than in HCF patients. A higher cardiovascular event rate observed in LCF patients was explained by older age and other cardiovascular risk factors at baseline. In LCF patients, the MMSE score declined less in the candesartan than in the control group (mean difference 0.49, 95% confidence interval 0.02 to 0.97, P = .04). Nonfatal stroke was reduced in the candesartan group in the total sample (28%, P = .04), with no difference between LCF (27%) and HCF (29%) patients. CONCLUSIONS: Elderly patients with mild-to-moderate hypertension and slightly impaired cognitive function (MMSE 24 to 28) are at increased risk of dementia and cardiovascular events. This analysis indicates that effective antihypertensive therapy may reduce cognitive decline and stroke incidence in these patients.

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The Study on COgnition and Prognosis in the Elderly (SCOPE) assessed the effect of candesartan on cardiovascular outcomes in elderly patients with mild to moderate hypertension. Patients were randomized to candesartan 8-16 mg daily (n = 2477) or placebo (n =2460). Due to extensive add-on therapy, blood pressure reduction was only about 3/2 mmHg greater in the candesartan group than in the control group. Nevertheless, non-fatal stroke was reduced by 28% (p = 0.04) in the candesartan group compared to the control group, and there was a non-significant 11% reduction in major cardiovascular events (p = 0.19). This report provides results in pre-specified subgroups of patients (age, gender, diabetes, history of stroke, smoking and cardiovascular risk at randomization). Reductions in major cardiovascular events and stroke with candesartan-based therapy were indicated in all subgroups. A significant interaction between treatment and subgroups was found for one pair of subgroups only; the reduction in major cardiovascular events with candesartan was greater in patients with a previous stroke (64% reduction, p = 0.004) than in those without (5% reduction, p > 0.20). In conclusion, this analysis indicated consistent favourable effects of candesartan-based therapy on major cardiovascular events and stroke across the different subgroups of patients. However, the benefit was particularly pronounced in patients who entered the study with a previous stroke.

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OBJECTIVES: The aim of this study was to test the hypothesis that the angiotensin II type 1 receptor blocker (ARB) candesartan can reduce the risk of stroke in elderly patients with isolated systolic hypertension (ISH). BACKGROUND: Isolated systolic hypertension is the predominant form of hypertension in the elderly, and stroke is the most common cardiovascular (CV) complication. METHODS: In the Study on Cognition and Prognosis in the Elderly (SCOPE), 4,964 patients age 70 to 89 years were randomly assigned to double-blind candesartan or placebo with open-label antihypertensive therapy (mostly thiazide diuretics) added as needed to control blood pressure. Of the 4,964 patients, 1,518 had ISH (systolic blood pressure >160 mm Hg and diastolic blood pressure <90 mm Hg). The present study is a predefined subgroup analysis of outcome results in the ISH patients. RESULTS: Of the ISH patients, 754 were randomized to the candesartan group and 764 to the control group. Over the study period, blood pressure was reduced by 22/6 mm Hg in the candesartan group and by 20/5 mm Hg in the control group (difference between treatments 2/1 mm Hg; p = 0.101 and 0.064). A total of 20 fatal/non-fatal strokes occurred in the candesartan group (7.2/1,000 patient-years) and 35 in the control group (12.5/1,000 patient-years); relative risk (RR) was 0.58 (95% confidence interval 0.33 to 1.00), that is, a RR reduction of 42% (p = 0.050 unadjusted, p = 0.049 adjusted for baseline risk). There were no marked or statistically significant differences between the treatment groups in other CV end points or all-cause mortality. CONCLUSIONS: In elderly patients with ISH, antihypertensive treatment based on the ARB candesartan resulted in a significant 42% RR reduction in stroke in comparison with other antihypertensive treatment, despite little difference in blood pressure reduction.

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OBJECTIVE: To assess clinical outcomes in the Study on COgnition and Prognosis in the Elderly (SCOPE) in patients who did not receive add-on antihypertensive therapy after randomization, i.e. in patients that best reflect the original intention of a placebo-controlled trial. DESIGN: Post-hoc analysis of a prospective, randomized, controlled trial. SETTINGS AND PARTICIPANTS: Five hundred and twenty-seven centres in 15 countries participated in SCOPE. Patients aged 70-89 years, with systolic blood pressure 160-179 mmHg and/or diastolic blood pressure 90-99 mmHg, and preserved cognitive function were eligible. Out of 4937 patients in SCOPE, 2098 did not receive add-on therapy. INTERVENTION: The number of patients who received candesartan 8-16 mg once daily was 1253, and 845 received placebo. Mean follow-up was 3.7 and 3.5 years, respectively. MAIN OUTCOME MEASURES: Primary: major cardiovascular events (cardiovascular mortality, non-fatal stroke or non-fatal myocardial infarction). Secondary: total mortality, cardiovascular mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, cognitive function, and dementia. RESULTS: The treatment groups were generally well balanced for baseline characteristics. Blood pressure fell by 21.8/11.0 mmHg in the candesartan group and by 17.2/8.4 mmHg in the placebo group. There were significant relative risk reductions with candesartan in major cardiovascular events (32%, P = 0.013), cardiovascular mortality (29%, P = 0.049), and total mortality (27%, P = 0.018). There were no significant differences between the treatment groups in cognitive outcomes. Both treatments were generally well tolerated. CONCLUSIONS: Treatment of elderly patients with mild hypertension is beneficial and supports current recommendations. Candesartan appears an appropriate therapy in such patients, in view of its favourable tolerability profile and ability to reduce major cardiovascular events.

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