Does the time interval between sentinel lymph node biopsy and completion lymph node dissection affect outcome in malignant melanoma? A retrospective cohort study.

Nodal clearance was recommended after positive sentinel lymph node biopsy (SLNB) despite further metastases to the regional lymph node basin being found in only 6-21% in the literature. This retrospective study was conducted to determine the role of the time interval between excision of primary melanoma and confirmed metastasis in the sentinel lymph node biopsy as well as the one between positive sentinel lymph node biopsy (SLNB-positive patients) and subsequent completion lymph node dissection (CLND) on the presence of metastases. The monocentric analysis included 121 patients with a history of completion lymph node dissection after positive SLNB from January 2005 to October 2013. Additional metastases in the regional lymph node basin (non-sentinels) were found in 14.05% (n = 17). Significant risk factors for the presence of metastases in CLND were the time between confirmed primary tumour to metastasis in sentinel lymph nodes (SLN) (p = 0.0034), N-category of TNM-classification (p = 0.0066) and independent of thickness of primary tumour (p = 0.11). If SLNB was performed up to forty-three days after confirmed primary melanoma, subsequent lymph node dissection was positive in less than 9.1%. When SLNB was performed with a delay of more than 80 days, all patients had metastases in the CLND specimens. Our data analysis suggests that delays in subsequent procedures of SLNB after diagnosis of primary melanoma may have a greater impact on positivity of non-sentinel lymph nodes than previously assumed. Our retrospective analysis may indicate the reconsideration of time schedule in the management of primary melanoma to potentially avoid local relapse in the draining lymph node region after positive SLNB.

Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells.

BACKGROUND: Lysine-specific demethylase 1 (LSD1 or KDM1A) overexpression correlates with poor survival and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling promoting c-MYC expression. We examined the antitumor efficacy of LSD1 inhibition with HCI-2509 in advanced stages of prostate cancer. METHODS: Cell survival, colony formation, histone methylation, c-MYC level, c-MYC expression, cell cycle changes and in vivo efficacy were studied in castration-resistant prostate cancer cells upon treatment with HCI-2509. In vitro combination studies, using HCI-2509 and docetaxel, were performed to assess the synergy. Cell survival, colony formation, histone methylation and c-myc levels were studied in docetaxel-resistant prostate cancer cells treated with HCI-2509. RESULTS: HCI-2509 is cytotoxic and inhibits colony formation in castration-resistant prostate cancer cells. HCI-2509 treatment causes a dose-dependent increase in H3K9me2 (histone H3lysine 9) levels, a decrease in c-MYC protein, inhibition of c-MYC expression and accumulation in the G0/G1 phase of the cell cycle in these cells. PC3 xenografts in mice have a significant reduction in tumor burden upon treatment with HCI-2509 with no associated myelotoxicity or weight loss. More synergy is noted at sub-IC50 (half-maximal inhibitory concentration) doses of docetaxel and HCI-2509 in PC3 cells than in DU145 cells. HCI-2509 has growth-inhibitory efficacy and decreases the c-myc level in docetaxel-resistant prostate cancer cells. CONCLUSIONS: LSD1 inhibition with HCI-2509 decreases the c-MYC level in poorly differentiated prostate cancer cell lines and has a therapeutic potential in castration- and docetaxel-resistant prostate cancer.

Treatment of hyperlipidemia in primary practise in Germany: sub-group analyses from the 4E-registry with particular emphasis on men and women with diabetes mellitus.

AIMS: To investigate the achievement of treatment goals for low density lipoprotein (LDL) cholesterol in men and women with diabetes mellitus receiving statins in a primary-care setting in Germany. METHODS: 6,827 men and 5,989 women with diabetes mellitus were recruited from among the 28,200 men and 24,200 women participating in the 4E registry of patients being treated with statins for primary hypercholesterolemia unresponsive to diet and lifestyle. Participants were assessed after 6 weeks and 9 months of statin therapy. Attainment of treatment targets was assessed (i) using individual LDL goals based on each participant's individual level of risk and (ii) based on the 2.6 mmol/L target recommended by current European and U.S. guidelines for persons with diabetes. RESULTS: At baseline, patients with and without diabetes mellitus had similar LDL cholesterol levels patients (men: 4.5+/-1 vs. 4.7+/-1 mmol/L, women: 4.7+/-1 vs. 4.9+/-1 mmol/L respectively). The mean drop in LDL cholesterol on statin therapy was similar in men and women with and without diabetes, ranging from 26-27 percent all subgroups. After 9 months of statins, individual LDL goals were achieved by 25% of men and 24% of women with diabetes, while only 16% of diabetic men and 12% of diabetic women achieved the 2.6 mmol/L LDL target. These success rates were similar to those of non-diabetics, including those at high risk, in 4E. CONCLUSIONS: Patients with diabetes mellitus in 4E responded just as well to statins as patients without diabetes. However, achievement of treatment goals in patients with diabetes was just as poor as in other high-risk groups in the 4E cohort.

Posttranslational regulation of Neurospora circadian clock by CK1a-dependent phosphorylation.

Frequency (FRQ) and its transcriptional activator, the White Collar Complex (WCC), are essential components of interconnected feedback loops of the circadian clock of Neurospora. In a negative feedback loop, FRQ inhibits the WCC by recruiting casein kinase 1a (CK1a) and supporting its phosphorylation. In an interconnected positive loop, FRQ supports accumulation of high levels of WCC. Phosphorylation of clock proteins is crucial for the temporal and spatial coordination of these functions. We identified three isoforms of CK1a generated by alternative splicing that all interact with FRQ. Furthermore, we show that WC-2 is phosphorylated by CK1a in vitro and that WC-2 phosphorylation is inhibited in vivo by the CK1-specific inhibitor IC261. Finally, we demonstrate that CK1a activity regulates levels of WC-2.

Relapses and subsequent worsening of disability in relapsing-remitting multiple sclerosis.

OBJECTIVE: To investigate whether relapses contribute to the development of subsequent sustained increase of impairment and disability in patients with multiple sclerosis (MS). METHODS: In a random sampled subset of 256 relapsing-remitting MS (RRMS) patients from the placebo arms of 20 randomized, controlled clinical trials contained in the Sylvia Lawry Centre for MS Research (SLCMSR) open database (mean follow-up time 2.66 years), the authors tested whether time to an increase of the Expanded Disability Status Scale (EDSS) score (confirmed after 6 months) was related to the occurrence of prior relapses. In the primary analysis, EDSS progressions starting within the period used to calculate the on-study relapse rate (sacrifice period) were not counted. The result obtained was then validated in an independent validation part of the SLCMSR database (n = 320). RESULTS: Although in the first subset of 256 RRMS patients, occurrence of relapses in the first 4 months on study appeared to be the best predictor for a shorter time to subsequent sustained increase in the EDSS score (hazard ratio [HR] 2.26 [95% CI: 1.36 to 3.75]), this finding was not confirmed in the validation dataset (HR 1.35, one-sided Wald test, lower limit of the 95% CI: 0.90). CONCLUSION: Although relapses may result into permanent damage and Expanded Disability Status Scale (EDSS) progression, there is no consistent effect of on-study relapses on the subsequent development of sustained EDSS score increase during a typical clinical study observation period.

[Impact of universal varicella vaccination in Germany: an epidemiological and economic analysis]. / Effektivität einer universellen Varizellen-Schutzimpfung in Deutschland: Eine epidemiologische und gesundheitsökonomische Analyse.

Varicella is a highly contagious viral disease which mainly affects young children and usually is perceived as infection with a mild disease course. However, there is increasing evidence indicating that the morbidity and mortality as well as the economic impact associated with varicella are significant. While universal childhood vaccination against varicella is currently not recommended in Germany, the availability of safe and efficacious vaccines offers the opportunity for preventive intervention. Detailed and reliable data on the consequences of varicella and the possible impact of a universal vaccination program are missing to date for Germany. In order to generate this information, we conducted a comprehensive evaluation. The objective was to quantify the medical consequences and the economic impact of varicella on third-party payers and the society by means of a model analysis, and particularly to assess the effects of various universal vaccination strategies. The study confirms that varicella represents a significant health and economic burden in Germany. Following mathematical modelling, universal varicella vaccination for children at the age of 12-18 months could prevent more than 82 % of cases and complications on average per year. Economically, universal vaccination would lead to net cost savings not only for the society but also for the third-party payers. From these findings it can be concluded that universal varicella vaccination is a strategy which should be encouraged, from a medical, epidemiological, but also economic viewpoint.

[MS registry in Germany--design and first results of the pilot phase]. / MS-Register in Deutschland -- Design und erste Ergebnisse der Pilotphase.

In the summer of 2001, a nationwide epidemiological multiple sclerosis (MS) register was initiated under the auspices of the German MS Society (DMSG). This project aimed at collecting epidemiological data on the number of patients with MS, course of the disease, and their social situation in Germany. During the 2-year pilot phase, five MS centers with various regional differences and treatment methods participated, leading to a representative selection of patients. In December 2003, standardised data sets of 3,458 MS patients were available for evaluation. After examining the quality of the data, 3,223 sets remained for further analysis. The demographics were similar to those obtained from other epidemiological studies: 72% of the patients were female, mean age was 42.9+/-11.2 years, mean disease duration 12.6+/-8.7 years, and 64% suffered from the relapsing-remitting form of the disease. The median EDSS was 3.0, and 69% of patients had an EDSS

Effects of varicella vaccination on herpes zoster incidence.

The effects of a general varicella vaccination programme on the incidence of herpes zoster are of major public health importance. This review focuses on two key aspects, namely the relationship between wild-type virus spread and the incidence of herpes zoster, as obtained from recent surveys, surveillance and observational studies, and the results from mathematical population models. Although knowledge is limited, close contact with varicella cases seems to have a protective effect. Thus, an increase in zoster incidence after varicella immunisation is possible, but the extent is unknown because of the influence of other factors independent of immunisation. Currently, vaccination effects estimated from mathematical modelling depend strongly on pre-specified assumptions. In order to obtain more precise predictions, the results of ongoing monitoring and clinical studies are awaited and further studies are suggested. Vaccination recommendations can be adapted at any time to take account of further findings in this area.

Empirical data on the varicella situation in Germany for vaccination decisions.

As epidemiological data concerning varicella in Germany were not available, a retrospective study was conducted to investigate the impact of the disease, focusing also on economic aspects. A representative German-wide sample of 1334 unvaccinated varicella cases was obtained in 1999 from randomly selected paediatric (P) and general, as well as internal, mainly adult (A), practices. Following representative weighting, the median age was 5 years, with 90% of cases aged < 12 years. The highest incidence was in children aged 5-6 years. Varicella-related complications occurred in 5.7% of patients, and accounted for 0.1 hospital days/case on average. Certificates of sick leave were issued for 1.3 sick days/case, with 0.6 days paid by health insurance funds to parents caring for their sick child, and 0.7 days paid by the employer. With an annual incidence of 760,000 diagnosed cases in Germany for the year 1999, this amounts to an annual cost of c.150 million Euro, with c. 50 million Euro paid by the statutory health insurance system. It was concluded that universal varicella vaccination in Germany would provide essential clinical improvements for patients and prevent hospital admissions. In addition, significant economic benefits can be expected, mainly because of the high level of indirect health costs in Germany.

The cost-effectiveness of routine childhood varicella vaccination in Germany.

This study explores the economic value of a routine varicella vaccination program for Germany. An age-structured decision analytic model was used to assess the benefits, costs and cost-effectiveness of an immunization program for a period of 30 years. Three interventions were compared with no vaccination: universal vaccination of around 15 months old healthy children, vaccination of susceptible adolescents (11-12 years of age), and the combined strategy. The analysis was conducted from both the societal perspective and the payers', i.e. sickness funds, perspective. Input data were mainly derived from a retrospective survey (analyzed were 1334 patient records) and from a seroprevalence study (n = 4602 sera). Using a coverage rate of 85% and a vaccine efficacy rate of 86% routine children vaccination could prevent around 611,000 varicella cases and over 4700 major complications per year. Average yearly cost savings for the society are 51.3 million Euro. The benefit-cost ratio (BCR) is 4.12. From the third-party payer's perspective, the BCR is 1.75 which is a consequence of significant reimbursement of parent's lost earnings by German sickness funds. The adolescent vaccination strategy has a favorable BCR ratio of 8.44 from the societal perspective, but clearly inferior medical effects. The combined vaccination strategy showed similar results as the children strategy. Routine childhood varicella vaccination appears to be a highly efficient strategy to reduce the burden of varicella and results in significant savings for both the society and the payers.

Lipid-lowering medication for secondary prevention of coronary heart disease in a German outpatient population: the gap between treatment guidelines and real life treatment patterns.

BACKGROUND: Few published data in particular from the United States indicate that the implementation of guidelines for prevention of coronary heart disease (CHD) is far from optimal. The objective of our study was to identify the type and prevalence of lipid-lowering medications in a German outpatient CHD population and to examine the impact of applied treatment regimens on serum lipid levels. METHODS: Retrospective analysis of the washout phase of 2,856 CHD patients requiring lipid-lowering medication. Data are derived from a multicenter, randomized, open-label, parallel group clinical trial comparing the safety and efficacy of atorvastatin versus simvastatin in 591 centers in Germany. Medical history, physical examination, and serum lipid levels were obtained at the beginning of the washout phase (Week -6) and at the end of the washout phase (Week -1, i.e., 5 weeks after the discontinuation of all prior lipid-lowering medications). The data at Week -6 represented the lipid levels under real life conditions. The difference from the data at Week -1 reflected the therapeutic effects achieved by the previous lipid-lowering treatment. RESULTS: The mean low-density lipoprotein cholesterol (LDL-C) level at Week -6 was 173.4 +/- 42.5 mg/dl. Only 176 (6.2%) of 2,856 CHD patients were found to meet the target LDL-C level of <115 mg/dl at Week -6, only 76 (2.7%) patients had LDL-C levels <100 mg/dl, and 363 (12.7%) patients had LDL-C levels <130 mg/dl. After discontinuation of all prior lipid-lowering medications, mean LDL-C increased to 187.2 +/- 44.0 mg. This means that only a marginal 7.4% reduction in LDL-C level was achieved under real life treatment conditions. This limited LDL-C reduction was due mainly to the low prevalence of lipid-lowering treatment (65.5% of patients did not receive any medication at all) and inadequate dosing. With respect to the effect on LDL-C and total cholesterol, statins alone were superior to fibrates. CONCLUSION: The study shows that there is a wide gap between treatment guidelines and real life treatment patterns in Germany. Awareness of the risks of high cholesterol levels has to be increased among both patients and physicians. Available treatment guidelines should be better implemented.

Complications, co-morbidity, and blood glucose control in type 2 diabetes mellitus patients in Germany--results from the CODE-2 study.

In this study, prevalence and incidence of complications as well as co-morbidity in type 2 diabetes patients in Germany were evaluated as part of a cost-of-illness study (CODE-2(TM), Costs of Diabetes in Europe - Type 2)In a pre-study, 197 general practitioners and diabetes specialists all over Germany provided data on the complication status of 2701 randomly selected patients with type 2 diabetes. The patients were grouped into five mutually exclusive strata. This pre-study was performed to generate a general overview on complication status to select proper patients for the main study. The main study was performed on stratified samples derived from the pre-study. Irrespective of the real prevalence of the five strata, an equal number of 160 were randomly selected from each stratum. Thus, rare complications were also covered in the study. Data from 809 patients were collected retrospectively on the basis of medical files during interviews with the physician. To achieve representative estimates of absolute prevalence and incidence of diabetes-related complications in Germany, results were weighted using frequencies of the strata. Severe complications were diagnosed in 50% of these patients. Prevalences were: 10.56% myocardial infarction, 6.66% stroke, 3.97% foot ulcer, 2.30% amputations and 1.34% blindness. Overall incidences in the diabetes population were estimated at 0.78% myocardial infarction, 1.28% stroke and 0.80% amputations. 23% of the diabetes patients suffered from 2 or more complications. The complication status became considerably worse with increasing time since the diagnosis of diabetes. The mean HbA1c level was 7.51% (i.e. 122% of the upper limit of the respective normal ranges). The presence of complications and co-morbidity in type 2 diabetes patients was a frequent finding. This underlines the importance of complications in diabetes patients and the necessity to increase any means of prevention in order to relieve the personal and economic burden of type 2 diabetes.

[Costs of type 2 diabetes in Germany. Results of the CODE-2 study]. / Kosten des Typ-2-Diabetes in Deutschland. Ergebnisse der CODE-2-Studie.

BACKGROUND AND OBJECTIVE: Diabetes is an increasing and widespread chronic disease causing considerable costs for the health care system. In the CODE-2 Study (Costs of Diabetes in Europe-Type 2) the total expenses for type 2 diabetics in Germany were evaluated and analyzed for the first time. PATIENTS AND METHODS: The CODE-2-study has been performed in eight European countries. In the German arm of the study, medical, demographic, and economic data of 809 patients were obtained retrospectively for a one year period, using face-to-face interviews with 135 physicians. These results were projected for the overall population of type 2 diabetes patients in Germany. RESULTS: The annual costs caused by type 2 diabetes patients in Germany in 1998 amount to 31.4 billion DM. The majority of these costs (61%) were covered by statuatory and private health insurance. The annual expenses of the statuatory Health Insurance (SHI) for these patients amounted to 18.5 billion DM. These costs divided in 50% spent for inpatient treatment, 13% for ambulatory care, and 27% for medication. Diabetes medication (insulin, oral antidiabetic drugs) accounted for only 7% of total SHI costs. Only 26% of all diabetic patients were adjusted to HbA1c values < 6.5% according to the therapeutic targets of the European Diabetes policy group. 50% of the type 2 diabetic patients exhibited severe macro- and/or microvascular complications. The costs per patient--compared to the average expenses for SHI insured patients--increased with complication state from the 1.3-fold (no complications) up to the 4.1-fold (macro- and microvascular complications). CONCLUSIONS: The overall costs for patients with type 2 diabetes are higher than expected from previous estimates. Diabetes related complications and concomitant diseases are the predominant reasons for these high costs. Control of blood glucose is inadequate for the majority of diabetic patients. To prevent long-term complications, an optimized treatment of type 2 diabetes is imperative not only from a medical but also from a health economics point of view.

The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial.

The effect of an adjuvant mistletoe extract treatment was tested in a prospective, randomised controlled clinical trial involving 477 patients with head and neck squamous cell carcinoma. The patients were stratified into two treatment groups that underwent surgery or surgery followed by radiotherapy and both groups were randomised for additional treatment with mistletoe extract. Patients treated with a mistletoe lectin-1 (ML-1) standardised mistletoe preparation had no lower risk of local/locoregional recurrences, distant metastases or second primaries. In the main analysis based on 202 patients treated with surgery and 275 patients treated with surgery and radiotherapy the adjusted hazard ratio for the disease-free survival (DFS) was 0.959 (95% confidence interval (CI) 0.725-1.268). The 5-year survival rates of patients from the mistletoe group were no better than the survival rates of patients from the control group. Furthermore, no significant changes in the cellular immune reaction or in quality of life could be detected. We conclude that the used mistletoe preparation has no indication in the adjuvant treatment of patients with head and neck cancer.

[Guidelines for lowering lipids are too infrequently observed. Results of a retrospective study of coronary heart disease patients]. / Leitlinien zur Lipidsenkung zu wenig beachtet. Ergebnisse einer retrospektiven Analyse an KHK-Patienten.

UNLABELLED: The aim of this retrospective analysis was to investigate adherence to treatment guidelines in the secondary prevention of coronary heart disease. 3720 CHD patients treated in 591 doctor's offices throughout Germany were investigated. End points were serum lipid levels at week-6, i.e. screening investigation, and 5 weeks after discontinuation of the lipid-lowering medication (week-1). 3383 of the 3720 (90.9%) patients had LDL-C levels > = 115 mg/dl, and 3563 (95.8%) > = 100 mg/dl. At week-6 mean LDL-C was 167.7 +/- 43.5 and mean total cholesterol was 258.8 +/- 47.8 mg/dl. 5 weeks after discontinuation of lipid-lowering treatment, mean LDL-C increased by 5.6%, and mean total cholesterol by 3.7% in comparison with baseline at week-6. 2346 (69.3%) of the patients with LDL-C > = 115 at week-6 did not receive any prior lipid-lowering medication. Also, patients receiving lipid-lowering medication demonstrated an insufficient lipid decrease (only 14.4% of all treated patients had LDL-C levels < 115 mg/dl, and only 6.8% had levels < 100 mg/dl. CONCLUSION: So far, lipid-lowering guidelines for the secondary prevention of CHD are not being adequately implemented. Appropriate action to remedy this situation (e.g. establishment of Disease Management Programs) is needed. The aggressive use of lipid-lowering drugs is a must if the goals of the treatment guidelines are to be met, and morbidity and mortality of CHD lowered.

Effects of lovastatin on progression of non-dilated and dilated coronary segments and on restenosis in patients after PTCA. The cholesterol lowering atherosclerosis PTCA trial (CLAPT).

OBJECTIVES: The Cholesterol Lowering Atherosclerosis PTCA Trial (CLAPT) is a prospective, randomized trial with blinded angiographic end-points to assess the effect of 2-year's treatment with lovastatin initiated 4 weeks prior to PTCA, compared to usual care on non-dilated coronary segments and on dilated coronary lesions in male patients with total cholesterol between 200 and 300 mg. dl(-1)who underwent elective PTCA. METHODS AND RESULTS: Two hundred and twenty six patients were randomized 4 weeks prior to PTCA to special care (diet plus lovastatin n=112) or usual care (diet; n=114). One hundred and ninety-nine patients underwent PTCA at baseline and were finally included in the study. Quantitative coronary angiographic assessment was performed on blinded cinefilms at baseline (PTCA) and repeated after 4 and 24 months in 91% and 81% of the patients. The primary end-point was a change in the mean segment diameter of non-dilated segments. The mean lovastatin dose was 33 mg. day(-1). Total- and LDL-cholesterol decreased by 21% and 29% in the special care group and by 7% and 11% in the usual care patients. After 2 years, the mean segment diameter of non-dilated segments decreased by 0.03 mm in the usual care group and 0.004 mm in the special care group (P=0.27). The decrease in the mean segment diameter of dilated lesions was 0.17 mm (usual care) and 0.06 mm (special care) (P=0.04) after 4 months; 0.16 mm (usual care) and 0. 002 mm (special care) after 24 months, respectively (P=0.05). In both groups, the mean segment diameter of dilated lesions increased between 4 and 24 months after PTCA compared to a decrease in mean segment diameter of non-dilated segments (P<0.05). Restenosis (>50% diameter stenosis at follow-up) occurred in 28.4% of usual care and 22.2% of special care patients (P=0.17). CONCLUSIONS: Lovastatin reduced the progression of dilated lesions in men with elective PTCA. Independent of treatment allocation, the dilated lesions regressed and the non-dilated segments progressed during the study follow-up. Four weeks of pre-treatment with lovastatin did not influence the rate of restenosis. Lovastatin had no statistically significant effect on non-dilated segments.

[Lipid intervention and coronary heart disease in men less than 56 years of age. The Coronary Intervention Study: CIS]. / Lipid-Intervention und koronare Herzkrankheit bei Männern unter 56 Jahren. Die Coronare Interventions-Studie: CIS.

UNLABELLED: The CIS was undertaken with the aim to evaluate the effects of lipid modifications on angiographic progression and regression of CAD in patients with CAD and hypercholesterolemia. The design included a multicenter randomized, double-blind, parallel, placebo-controlled comparison, with target and safety limits for adjusting the trial medication depending on the LDL cholesterol level (LDL-C) achieved, i.e., up to 40 mg of simvastatin (S) or placebo (P) daily, add-on medication (up to 3 x 4 g Colestyramin), and diet counselling. Male patients, average age 49 (< or = 56) years, were included with angiographic CAD and a screening total cholesterol of 207-350 mg/dl, who were not due to undergo coronary bypass surgery or PTCA, who did not suffer from serious other disease (e.g., diabetes mellitus), and who had not undergone coronary bypass surgery previously. RESULTS: All baseline variables were comparable in the treatment groups, with 129 patients taking S and 125 taking P. Of these 254 patients 217 had their final study visit and 207 underwent a second angiography after an average treatment time of 2.3 years under an average daily dose of 37 mg S. 205 pairs of films were available for analysis. Vital information was obtained of all patients until closure of the data bank, half a year after the last study angiography. Five deaths occurred within the study period, 12 through March 15, 1995 (S: 1/6, P: 4/6). 37 patients (S: 18, P: 19) discontinued trial drug and protocol. Concomitant CAD medication was comparable in both groups, except lipid-lowering add-on medication which was significantly higher in the P group (38% versus 13%). Significant changes in lipid levels, on treatment, were observed in the S group amounting to a mean difference in LDL-C of -35%, in Apo-Protein B (ApoB) of -30%, in VLDL-C of -37%, and in triglycerides (TG) of -27%, and in HDL-C of +6%, in comparison to the control group; these differences were even greater in 137 fully compliant patients: -41, -36, -39, -31, and +7%, respectively. Progression in the S group was significantly less, as defined by the two primary target criteria: 1) the minimum obstruction diameter (MOD), determined by quantitative coronary angiography (QCA), decreased about five times less in comparison to the control group (S: by -0.017; P: -0.0954 mm), and 2) the standardized visual global change score (GCS) deteriorated almost three times less in the S group (by +0.20) than in the P group (+0.58). Of the secondary target criteria, the mean lumen diameter (QCA) also developed a significant difference (S: -0.20; P: +0.23 mm; p = 0.0006) with a trend toward regression in the S group. The QCA-%-stenosis deteriorated three- to four-times less in the S group as compared to the control group (S: by 0.69%; P: by 2.73%; p = 0.0022), and the number of patients with angiographic progression was nearly halved (S: 30%; P: 56%; p < 0.0000). These differences were determined by intention to treat analysis (ITT), and they were obtained in spite of lipid lowering add-on medication in 38% of the P patients; they turned out to be more pronounced in 137 fully compliant patients, in an analysis "as treated". The mean decrease in LDL-C serum level caused by S was significantly correlated to the decrease in progression, and multivariate regression analysis of both treatment groups identified LDL-C (or ApoB) and TG as independent predictors of progression. Progression appeared to be most pronounced in low and medium sized lesions, and the beneficial effect of lipid intervention dominated in lesions with 12-56% QCA stenosis severity. A small fraction of patients who suffered from exercise-induced angina, with ST-segment-depression at the beginning of the study, experienced a significant improvement under S as compared to P treatment. Although the study was not designed to show differences in clinical events, the combined number of all major cardiovascular events tended to be less frequent in the S than in the C gr

Safety of low-density lipoprotein cholestrol reduction with atorvastatin versus simvastatin in a coronary heart disease population (the TARGET TANGIBLE trial).

Reduction in plasma lipids has been recognized as one of the primary cardiovascular risk reduction strategies in the secondary prevention of coronary heart disease (CHD). The primary end points of TARGET TANGIBLE were the safety (adverse events and laboratory measurements) and efficacy (responder rates) of therapy with atorvastatin versus simvastatin with the aim of achieving low-density lipoprotein (LDL) cholesterol lowering to < or =100 mg/dl (2.6 mmol/L). A total of 3,748 CHD patients with LDL cholesterol levels > or =130 mg/dl (3.4 mmol/L) entered a run-in diet phase of 6 weeks without any lipid-lowering drug therapy. At the end of the diet phase, 2,856 patients met the lipid criteria and were randomized to active treatment for 14 weeks. Patients received 10 to 40 mg of either drug in an optional titration design at 2:1 randomization for atorvastatin versus simvastatin. Adverse event rates were statistically equivalent (p<0.01) for simvastatin (35.7%) and for atorvastatin patients (36.3%). Both drugs were well tolerated; <5% of patients in both groups were withdrawn due to adverse events. In all, 37 atorvastatin patients (2%) and 27 simvastatin patients (3%) had serious adverse events. Drug-related side effects (elevations in creatine kinase, liver enzymes) occurred in both groups at similar rates with 10 atorvastatin patients (0.5%) and 5 simvastatin patients (0.5%) presenting confirmed transaminase elevations >3 x the upper limit of the normal range. Significantly fewer patients in the atorvastatin group (n = 724) required titration to 40 mg compared with the simvastatin group (n = 514) (38% vs. 54%, respectively; p<0.001). Atorvastatin resulted in a significantly greater number of patients reaching the LDL cholesterol goal than those treated with simvastatin, with 67% of atorvastatin patients and 53% of simvastatin patients reaching the target LDL cholesterol level of < or =100 mg/dl (2.6 mmol/L) (p<0.001). Both atorvastatin and simvastatin are safe for use by patients in the secondary prevention of CHD, with patients in both drug groups having similar adverse event rates. Despite the use of concomitant medications there was no drug-induced rhabdomyolysis with either atorvastatin or simvastatin.

A prognostic score for postherpetic neuralgia in ambulatory patients.

The main objective was to develop a scoring system for easy use by the physician in daily clinical practice in deciding the appropriate treatment for his herpes zoster patient. Data from 635 patients who did not receive antiviral therapy were included in this analysis. Of these, 131 developed postherpetic neuralgia (PHN). Of the 29 variables tested univariately in this study, 15 showed a significant correlation with the incidence of PHN, but only six proved to contribute to the overall predictive power in the multivariate approach. Using two independent approaches, the model showed a very satisfactory performance in the validation sample. Patients without acute pain rarely developed PHN. In those with acute pain, being female, being over 50 years of age, having more than 50 lesions, having lesions of a hemorrhagic nature, having cranial or sacral localisation of the rash or having pain in the prodromal phase proved to be significant, multivariate factors. An easy-to-use scoring system used in a risk graph is proposed. These data should be useful in the individual treatment decision as well as in the design and analysis of therapeutic trials in herpes zoster.