Long-term (6 and 12 months) follow-up of two prospective, randomized, controlled phase III trials of photodynamic therapy with BF-200 ALA and methyl aminolaevulinate for the treatment of actinic keratosis.

BACKGROUND: Two phase III trials of photodynamic therapy (PDT) with BF-200 ALA, a recently approved nanoemulsion formulation of 5-aminolaevulinic acid (ALA) demonstrated high clearance rates in mild-to-moderate actinic keratosis (AK). The comparison to a registered methyl aminolaevulinate (MAL) cream demonstrated significantly superior total patient clearance rates. OBJECTIVES: To evaluate long-term efficacy and safety of PDT for AK 6 and 12 months after the last PDT with BF-200 ALA, MAL or placebo. METHODS: The follow-up phase (FUP) was performed with patients of two phase III studies. Both studies compared BF-200 ALA with placebo, one of the studies additionally with MAL. Overall recurrence rates and various subgroups (light source, lesion severity, lesion location, complete responders after first PDT) were assessed 6 and 12 months after the last PDT. RESULTS: Recurrence rates were similar for BF-200 ALA and MAL, with a tendency to lower recurrence rates for BF-200 ALA. The proportion of patients who were fully cleared during PDT and remained completely clear for at least 12 months after PDT were 47% for BF-200 ALA (both studies) and 36% for MAL treatment. The subgroup that was illuminated with narrow wavelength LED lamps reached 69% and 53% for BF-200 ALA (both studies, respectively) and 41% for MAL. No safety concerns were reported. CONCLUSIONS: The FUP data confirmed the high efficacy and safety of PDT with BF-200 ALA. The slightly lower recurrence rates after BF-200 ALA treatment compared with MAL treatment enhanced the better treatment outcome due to the significantly superior efficacy.

Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo.

BACKGROUND: Photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) or its methylester [methyl-5-aminolaevulinate (MAL) or 5-amino-4-oxopentanoate] was recently ranked as first-line therapy for the treatment of actinic keratosis (AK) and is an accepted therapeutic option for the treatment of neoplastic skin diseases. BF-200 ALA (Biofrontera Bioscience GmbH, Leverkusen, Germany) is a gel formulation of ALA with nanoemulsion for the treatment of AK which overcomes previous problems of ALA instability and improves skin penetration. OBJECTIVES: To evaluate the efficacy and safety of PDT of AKs with BF-200 ALA in comparison with a registered MAL cream and with placebo. METHODS: The study was performed as a randomized, multicentre, observer-blind, placebo-controlled, interindividual trial with BF-200 ALA, a registered MAL cream and placebo in a ratio of 3:3:1. Six hundred patients, each with four to eight mild to moderate AK lesions on the face and/or the bald scalp, were enrolled in 26 study centres in Germany, Austria and Switzerland. Patients received one PDT. If residual lesions remained at 3months after treatment, PDT was repeated. RESULTS: PDT with BF-200 ALA was superior to placebo PDT with respect to patient complete clearance rate (78·2% vs. 17·1%; P<0·0001) and lesion complete clearance rate (90·4% vs. 37·1%) at 3months after the last PDT. Moreover, superiority was demonstrated over the MAL cream regarding the primary endpoint patient complete clearance (78·2% vs. 64·2%; P<0·05). Significant differences in the patient and lesion complete clearance rates and severity of treatment-related adverse events were observed for the narrow- and broad-spectrum light sources. CONCLUSIONS: BF-200 ALA is a very effective, well-tolerated new formulation for AK treatment with PDT and is superior to a registered MAL medication. Efficacies and adverse events vary greatly with the different light sources used.

A randomized, double-blind, vehicle-controlled, half-side comparison with a herbal ointment containing Mahonia aquifolium, Viola tricolor and Centella asiatica for the treatment of mild-to-moderate atopic dermatitis.

OBJECTIVE: Only a few clinical trials have been published on the topical treatment of atopic dermatitis with herbal ointments. An ointment containing extracts from Mahonia aquifolium, Viola tricolor and Centella asiatica has previously been studied in open uncontrolled trials with children. However, no data exist on adult patients in a randomized controlled trial. METHODS: A total of 88 patients with mild-to-moderate atopic dermatitis were enrolled in a double-blind, vehicle-controlled, randomized, half-side comparison. Patients between 18 and 65 years of age were treated for 4 weeks with an ointment containing Mahonia aquifolium, Viola tricolor and Centella asiatica. The primary endpoint was a summary score for erythema, edema/papulation, oozing/crust, excoriation and lichenification according to a 4-point scale. Secondary efficacy variables were assessment of pruritus severity (10 cm VAS) and a global assessment of effectiveness as well as tolerability. RESULTS: The study ointment reduced the primary and secondary endpoints slightly more than the base cream which was used as vehicle; the differences were not statistically significant. Since the climatic conditions during the study duration varied from very mild and sunny to very cold and dry, a post-hoc subanalysis was performed with a subset of 64 patients whose treatment was at a mean outside temperature of 10 degrees C or less. Under these conditions the primary endpoint showed high statistical significance. CONCLUSION: In this trial, an ointment containing Mahonia aquifolium, Viola tricolor and Centella asiatica could not be proven to be superior to a base cream for patients with mild-to-moderate atopic dermatitis. However, a subanalysis indicated that the cream might be effective under conditions of cold and dry weather.

A prospective study on the use of a non-adhesive gelling foam dressing on exuding leg ulcers.

OBJECTIVE: This non-comparative phase II study aimed to evaluate the safety and performance of a non-adhesive gelling foam dressing (GFD-N) in leg ulcer management. METHOD: Forty-six subjects with moderately to heavily exuding leg ulcers were treated with a regimen including GFD-N. Dressings were changed at least every seven days for four weeks or until healing. RESULTS: Mean GFD-N wear time was 3.2 days per subject. Mean wound area decreased from 10.1 cm2 at baseline to 5.1 cm2 at four weeks (p<0.001) and healed in five subjects (11%). The surrounding skin improved or remained stable in all but one subject. When compared with pre-study dressings, ulcer pain decreased for GFD-N, both with the dressing in place (p<0.001) and on dressing removal (p<0.001). Of final investigator ratings for 45 subjects, most were 'excellent' for ease of application (89%), ease of removal (96%), conformability (67%) and overall performance (58%). Five subjects experienced adverse events; none were serious or dressing-related. CONCLUSION: This small study demonstrates that GFD-N was safe, effective and convenient for wound healing, exudate management, pain/comfort and ease of use.

Reduction of gaseous microembolism during aortic valve replacement using a dynamic bubble trap.

Serious postoperative psycho-neurological dysfunction is at least partially attributed to the occurrence of gaseous microbubbles in the arterial line of extracorporeal circulation (ECC). Therefore, we investigated in a prospective randomized double blind study whether the usage of dynamic bubble trap (DBT) will reduce microbubble load of patients undergoing aortic valve replacement. Patients (n = 41) were divided into group I (GI, n = 22) with DBT introduced into the arterial line of ECC and group II (GII, n = 19) with placebo-DBT instead. Doppler ultrasonography was used for detection of microbubbles before and after DBT, and for detection of high intensity transient signals (HITS) within the middle cerebral artery. The recording time during ECC was divided into period 1 (P1, until aortic clamp removal) and period 2 (P2, clamp removal until the end of ECC). A significant reduction of microbubble load was found in GI only (p < 0.0001 for ECC; p < 0.0001 for P1; p < 0.0025 for P2). A significant difference in number of HITS between the groups was observed in P1 only (p < 0.002 left middle cerebral artery, p < 0.005 right middle cerebral artery), since in P2 the trapped air in left chamber can go to the supraaortal vessels without passing ECC. In conclusion the use of DBT cannot substitute careful venting after aortic declamping. Nevertheless, reduction of HITS in the cross-clamped period of ECC justifies the use of DBT in patients undergoing open chamber surgery.

Trapidil decreases the aggregation of platelets from heart transplant recipients ex vivo.

Heart transplant recipients show platelet hyperaggregability, which may be related to the incidence of graft vasculopathy. We investigated whether trapidil can inhibit the aggregation of platelets from these patients. Platelet count, mean platelet volume (MPV), and adenosine diphosphate (ADP)-induced platelet aggregation were determined in 18 heart transplant recipients and 12 healthy subjects. Additionally, platelet-rich plasma from the patients was incubated with trapidil or with saline, prior to measuring ADP-induced aggregation. The MPV was significantly greater in patients compared to controls (9.4+/-1.1 vs 8.5+/-0.7 fL; P=.01), and ADP-induced platelet aggregation was significantly increased in patients compared to controls (81.2%+/-13.1% vs 69.6%+/-16.2%; P=.04, respectively). The trapidil-treated samples showed significantly decreased platelet aggregation compared to the control samples (24.2%+/-12.6% vs 66.7%+/-11.7%; P<.001). Platelets from heart transplant recipients showed an increased MPV and increased ADP-induced aggregation. Trapidil effectively reduced the ADP-induced aggregation ex vivo.

Non-aneurysmal inflammation of the aorta in combination with aortic valve disease.

A 61-year-old man presented with aortic valve stenosis, coronary artery disease in combination with rheumatic arthritis, peri-aortic inflammation and fibrosis with aortitis. In the pathological literature this has been termed chronic periaortitis, while in the surgical literature, non-aneurysmal dilatation of the aorta associated with atherosclerosis and inflammation has been described as aortitis. The name chronic periarteritis refers to the associated involvement of coronary arteries. Although different terminologies have been used, it is suggested that all of them most likely represent the same disease entity.

Atrial fibrillation at discharge from the hospital in patients undergoing mitral valve repair.

BACKGROUND: Patients undergoing mitral valve repair (MVRr) are often discharged on oral anticoagulation with warfarin. Because the decision about oral anticoagulation is made at discharge from the hospital and because atrial fibrillation (AF) represents the only well-documented indication for oral anticoagulation in these patients, we studied the frequency of AF at discharge after MVRr. METHODS: We reviewed the records of 245 patients who underwent MVRr over the past 5 years and assessed the frequency of AF at discharge from the hospital and the factors that were associated with an increased risk for arrhythmia. RESULTS: The group comprised 95 women and 150 men with a mean age of 62.1 +/- 14 years. Seventy-three (30 %) patients were in and/or had a history of AF on admission. Sixty-five (27 %) patients had AF at discharge. Factors that were associated with AF at discharge were: AF on admission (odds ratio [OR] 57.1; confidence interval [CI] 20.8 - 157.3; p < 0.0001), enlarged left atrium (OR 3.2; CI 1.2 - 8.7; p = 0.025) and intake of ACE inhibitors (OR 3.9; CI 1.2 - 12.3; p = 0.022). The OR for AF at discharge in patients with none of the above risk factors was 0.02 (95 % CI 0.02 - 0.13; p < 0.0001). CONCLUSION: Only a relatively small proportion of the studied patients, especially patients with AF on admission, with larger atria and with a history of ACE inhibitors intake, were in AF at discharge after MVRr. Patients with none of these risk factors were at low risk for AF at discharge after MVRr and the optimal oral anticoagulation regimen for these low-risk patients needs to be determined.

Leukocyte-depleted secondary blood cardioplegia attenuates reperfusion injury after myocardial ischemia.

BACKGROUND: Activated neutrophils have been implicated in reperfusion injury of the myocardium; leukocyte depletion at the time of reperfusion may contribute to better myocardial protection after cardiac surgery. In the present study, we examined whether leukocyte depletion as an adjunct to terminal blood cardioplegia attenuates reperfusion injury. METHODS: Porcine hearts that had undergone 60 minutes of normothermic ischemia with cardioplegia and 60 minutes of reperfusion under cardiopulmonary bypass were divided into four groups according to the methods of 15 min of controlled initial reperfusion: whole blood reperfusion (n = 6), leukocyte-depleted reperfusion (n = 6), secondary blood cardioplegia (n = 6) and leukocyte-depleted secondary blood cardioplegia (n = 6). At 60 min of reperfusion, hemodynamic recovery, release of malondialdehyde (MDA) as a marker for free oxygen radicals, CK-MB-isoenzyme from the coronary sinus, recovery of adenosine triphosphate, and myocardial water content were evaluated. RESULTS: The group with leukocyte-depleted secondary blood cardioplegia showed the best hemodynamic recovery (Emax and total dp/dt), lowest levels of MDA, CK-MB and myocardial water content, and highest adenosine triphosphate recovery. CONCLUSIONS: These results suggest that controlled reperfusion with leukocyte-depleted secondary blood cardioplegia attenuated severe damage of the myocardium as compared to whole blood reperfusion.

INR self-management permits lower anticoagulation levels after mechanical heart valve replacement.

BACKGROUND: The Early Self Controlled Anticoagulation Trial (ESCAT I) showed that anticoagulation self-management after mechanical heart valve replacement decreased complication rates by maintaining INR levels closer to the target range than International Normalized Ratio (INR) home doctor management. The therapeutic range for the INR in that study was between 2.5 and 4.5 for all positions of prosthetic valves. ESCAT II should find out whether lowering the target range for INR self-management would further reduce complication rates. METHODS: ESCAT II is a prospective controlled randomized (valves: St. Jude Medical Standard or Medtronic Hall, treatment: conventional/low-dose) multicenter study with 3,300 patients. We present interim results of 1,818 patients. 908 were categorized as having a low-dose target range, which was INR 1.8 to 2.8 for prostheses in aortic position and 2.5 to 3.5 for prostheses in mitral position or in combined valve replacement. The control group (conventional group) with 910 patients aimed at an INR of 2.5 to 4.5 for all valve positions. RESULTS: In the conventional group, 74% of INR values measured were within the therapeutic range. In the low-dose group, 72% of the values were within that range. The linearized thromboembolism rate (% per patient year) was 0.21% for both groups. The bleeding complication rate was 0.56% in the low-dose regimen group versus 0.91% in the conventional group. CONCLUSIONS: Early onset INR self-management under oral anticoagulation after mechanical heart valve replacement enables patients to keep within a lower and smaller INR target range. The reduced anticoagulation level resulted in fewer grade III bleeding complications without increasing thromboembolic event rates.

Contrast-echocardiography: confirmation of patency of laser channels after transmyocardial laser revascularization.

AIMS: Apart from casuistic autopsy results there is no long-term evidence for channel perfusion after transmyocardial laser revascularization in humans. METHODS AND RESULTS: Fifteen consecutive patients aged 63+/-17 years were investigated 71+/-15 days after coronary artery bypass surgery and/or transmyocardial revascularization with 13-37 (20+/-5) channels (CO(2) laser, 40 J/pulse). Echocardiography was performed after injection of 6 ml echo contrast medium into left ventricular cavity and after injection of 3 ml contrast medium into the left main coronary artery. In five patients with additional bypass surgery to the same region, we also injected 3 ml contrast medium into bypass graft. We could prove in 10 of 15 patients (67%) one or two laser channels in the apical left ventricular myocardium. Channels were perfused exclusively during systole. During following heart cycles myocardium was opacified up to a mean width of 1.4+/-0.4 cm, a mean depth of 0.71+/-0.1cm, and a mean area of 1.0+/-0.6 cm(2). Contrast medium was washed out via coronary venous system in 9+/-8 systoles. CONCLUSION: This is the first clinical evidence of long-term laser-channel patency in humans showing perfused myocardium via left ventricular cavity.

Predictors for atrial transport function after mini-maze operation.

BACKGROUND: Restoration of atrial transport function (ATF) is a major goal of the maze procedure. This prospective study was undertaken to evaluate predictors of left atrial transport function in patients undergoing a mini-variant of the maze III procedure 3 and 12 months postoperatively. METHODS: Mini-maze operation was performed in 72 patients with a mean age of 64 +/- 8.7 years during a 5-year period. Seventy of 72 (97%) had combined procedures. Clinical and electrophysiologic examination was carried out before surgery, and 3 and 12 months postoperatively. RESULTS: Early mortality was 1.4% (1 of 72 patients) and late death occurred in 5.6% (4 of 71 patients). After 3 months, 54 of 68 (80%) patients showed sinus rhythm, and 48 of 60 (80%) after 12 months. ATF was restored in 87% (echocardiography) and 82% (magnetic resonance imaging) after 3 months, and in 86% (echocardiography) and 78% (magnetic resonance imaging) after 12 months. Independent predictors for ATF restoration after 12 months were better preoperative left ventricular function (p = 0.02), and smaller preoperative left atrial diameter (p = 0.005). Correlation between echocardiography and magnetic resonance imaging was 80% after 12 months. CONCLUSIONS: Restoration of ATF after mini-maze procedure is achieved in over 80%. Independent predictors for ATF restoration are smaller preoperative left atrial diameter and better preoperative left ventricular ejection fraction.

Ruptured papillary muscle after mitral valve replacement with preservation of chordae tendineae.

Many cardiac surgeons believe strongly that every effort should be made to preserve the continuity of the mitral anulus, chordae tendineae, and papillary muscles during mitral valve replacement in order to maximize ventricular function and maintain normal ventricular geometry. We treated a patient with spontaneous papillary muscle rupture after mitral valve replacement in whom efforts had been made to preserve continuity of the mitral mechanism.

[Papillary muscle rupture after mitral valve replacement with preservation of subvalvular structures]. / Papillarmuskelruptur nach Mitralklappenersatz mit erhaltenem subvalvulärem Apparat.

We report a female patient with mitral valve replacement and preservation of subvalvular apparatus in which parts of the papillary muscle ruptured postoperatively. During systole the ruptured papillary muscle prolapsed through the native aortic valve. Echocardiographic documentation and operative procedure were demonstrated.

Peripheral arterial embolism originating from a thrombus in the ascending aorta.

A 45-year-old man experienced arterial thromboembolism to the right leg requiring surgical restoration of blood flow. Transesophageal echocardiography (TEE) was performed to determine the source of embolism and identified a localized atherosclerotic lesion in the distal ascending aorta with an adherent, highly mobile thrombus. The patient underwent surgery with removal of the atherosclerotic plaque and attached thrombus, and resection of the adjacent aortic wall. This case illustrates an unusual location for a complex atherosclerotic lesion in the ascending aorta, and points out the opportunity for remedial surgery once a symptomatic embolus has occurred.

Significant reduction of air microbubbles with the dynamic bubble trap during cardiopulmonary bypass.

Air microbubbles mostly occur unnoticed during cardiopulmonary bypass and are predominantly responsible for serious postoperative psychoneurological dysfunction. A dynamic bubble trap (DBT), which removes air microbubbles from the arterial blood, was tested in a clinical study. The aim was to evaluate the efficiency of microbubble removal under clinical conditions. As blood passes through the DBT, which is placed in the arterial line between the arterial filter and arterial cannula, it is converted into a rotating stream. The bubbles are directed to the centre of the blood flow and are collected in the distal end of the DBT, from where they are returned to the cardiotomy reservoir. Doppler ultrasonography was used to detect the microbubbles before and after the DBT, and also the number of high-intensity transient signals (HITS) in the right and left middle cerebral artery during extracorporeal circulation. A significant reduction of microbubbles in the arterial line (3,990 before DBT, 537 after, p < 0.001) and HITS in the brain (51 in the DBT group, 77 in the placebo group, p = 0.04) was measured.

Effective treatment of leg vein telangiectasia with a new 940 nm diode laser.

BACKGROUND: A variety of lasers have been used in an attempt to treat leg vein telangiectasia OBJECTIVE: To evaluate the feasibility of a new 940 nm diode laser for the treatment of leg vein telangiectasia. METHODS: Thirty-one patients with leg vein telangiectasia were treated with a diode laser; 26 of these with 940 nm, 300-350 J/cm2, 40-70 msec, 1.0 mm handpiece, one pass, and 5 of these with 940 nm, 815 J/cm2, 50 msec, 0.5 mm handpiece, one pass. Each subject had three treatments of the same site at 4-week intervals. Photographs taken before and 4 weeks after the last treatment were evaluated by two independent observers for vessel clearance. RESULTS: In those 26 patients treated with a fluence of 300-350 J/cm2, a vessel clearance of greater than 50% was achieved in 20 patients (76%), 12 of these patients had clearance rates greater than 75%. A clearance rate of less than 50% was obtained in six patients, with three of these patients showing responses of less than 25%. In five patients treated with a fluence of 815 J/cm2 a clearance rate of more than 75% was observed. CONCLUSIONS: In this preliminary study a 940 nm diode laser was shown to be safe and effective for the treatment of leg vein telangiectasia.