A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies.

BACKGROUND: Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours. METHODS: Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course. RESULTS: Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile. CONCLUSIONS: These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients.

10-year follow-up of interventional electrophysiology: updated German survey during the COVID-19 pandemic.

INTRODUCTION: This study provides an update of survey-based data providing an overview of interventional electrophysiology over the last decade. Overall infrastructure, procedures, and training opportunities in Germany were assessed. METHODS: By analyzing mandatory quality reports, German cardiology centres performing electrophysiological studies were identified to repeat a questionnaire from 2010 and 2015. RESULTS: A complete questionnaire was returned by 192 centers performing about 75% of all ablations in Germany in 2020. In the presence of the COVID-19 pandemic, a total of 76.304 procedures including 68.407 ablations were reported representing a 38% increase compared to 2015. The median number of ablations increased from 180 in 2010 to 377 in 2020. AF was the most common arrhythmia ablated (51 vs. 35% in 2010). PVI with radiofrequency point-by-point ablation (64%) and cryo-balloon ablation (34%) were the preferred strategies. Less than 50 (75) PVI were performed by 31% (36%) of all centres. Only 25 and 24% of participating centres fulfilled EHRA and national requirements for training centre accreditation, respectively. There was a high number of EP centres with no fellows (38%). The proportion of female fellows in EP increased from 26% in 2010 to 33% in 2020. CONCLUSION: Comparing 2020, 2010 and 2015, an increasing number of EP centres and procedures were registered. In 2020, more than every second ablation was for therapy of AF. In the presence of an increasing number of procedures, training opportunities were still limited, and most centres did not fulfill recommended EHRA or national requirements for accreditation.

[Efficiency potential in the pacemaker/implantable cardioverter defibrillator outpatient clinic]. / Effizienzpotential in der Nachsorge von Schrittmachern und implantierbaren Kardioverter Defibrillatoren.

The aim of the present study was to elucidate whether the duration of a technical follow-up (FU) of a pacemaker (PM)/implantable cardioverter defibrillator (ICD) has an impact on cost-effectiveness in the outpatient clinic. We determined the time required for a complete FU of devices from three different manufacturers. In 130 patients (70 VVI/DDD-PM, 60 VVI/DDD-ICD) with either a PM (Phylos, Chorum/Talent, Kappa, EnPulse) or an ICD (Belos, Alto or GEM) the time was recorded for a complete FU including determination of lead impedance, sensing and pacing threshold. The time for activation of individual menue buttons was excluded. On the basis of time required for FU, cost-units (CU) were calculated for 2000 FU/year and for a presumed device longevity (PM 7 years, ICD 5 years). For VVI-PM, the duration of FU was almost identical for devices from different manufacturers (105+/-11 s to 125+/-8 s; p=n.s.). However, analysis of DDD-PM revealed marked differences (140+/-25 s vs 282+/-23 s, p<0.05). Time for FU of ICDs varied between 108+/-5 s and 207+/-21 s (p<0.05) in VVI-ICDs and between 129+/-8 ms and 225+/-23 s (p<0.05) in DDD-ICDs. The total savings could be 55 000 CU in VVI- and 53 333 CU in DDD-ICDs. For full automatic DDD-pacemakers (EnPulse) time for FU could be reduced to 58+/-3 s (p<0.05). Differences in FU times were caused by problems with telemetry, delay during booting of the programmer, interrogation at the beginning and at the end of FU and for sensing tests. Improving not only programmers and devices but also test automaticity could significantly increase cost-efficiency in the outpatient clinic.

Intercaval block in normal canine hearts : role of the terminal crest.

BACKGROUND: The intriguing monotony in the occurrence of intercaval conduction block during typical atrial flutter suggests an anatomic or electrophysiological predisposition for conduction abnormalities. METHODS AND RESULTS: To determine the location of and potential electrophysiological basis for conduction block in the terminal crest region, a high-density patch electrode (10x10 bipoles) was placed on the terminal crest and on the adjacent pectinate muscle region in 10 healthy foxhounds. With a multiplexer mapping system, local activation patterns were reconstructed during constant pacing (S(1)S(1)=200 ms) and introduction of up to 2 extrastimuli (S(2), S(3)). Furthermore, effective refractory periods were determined across the patch. If evident through online analysis, the epicardial location of conduction block was marked for postmortem verification of its endocardial projection. Marked directional differences in activation were found in the terminal crest region, with fast conduction parallel to and slow conduction perpendicular to the intercaval axis (1.1+/-0.4 versus 0.5+/-0.2 m/s, P<0.01). In the pectinate muscle region, however, conduction velocities were similar in both directions (0.5+/-0.3 versus 0.6+/-0.2 m/s, P=NS). Refractory patterns were relatively homogeneous in both regions, with local refractory gradients not >30 ms. During S(3) stimulation, conduction block parallel to the terminal crest was inducible in 40% of the dogs compared with 0% in the pectinate muscle region. CONCLUSIONS: Even in normal hearts, inducible intercaval block is a relatively common finding. Anisotropic conduction properties would not explain conduction block parallel to the intercaval axis in the terminal crest region, and obviously, refractory gradients do not seem to play a role either. Thus, the change in fiber direction associated with the terminal crest/pectinate muscle junction might form the anatomic/electrophysiological basis for intercaval conduction block.

Rate- and site-dependent effects of propafenone, dofetilide, and the new I(Ks)-blocking agent chromanol 293b on individual muscle layers of the intact canine heart.

BACKGROUND: Recent in vitro studies have demonstrated regional differences in electrophysiological properties of individual left ventricular muscle layers. Controversy exists on the relevance of these findings for the situation in vivo. Thus, this study was designed to determine whether the in vivo canine heart exhibits regional differences in left ventricular refractoriness and in the susceptibility to sodium and potassium channel blockers. METHODS AND RESULTS: In 16 dogs, 36 needle electrodes (12 mm long, 4 bipolar electrodes, interelectrode distance 2.5 mm) were inserted into the left ventricular wall. By use of a computerized multiplexer-mapping system, the spread of activation in epicardial, endocardial, and midmyocardial muscle was reconstructed during ventricular pacing at 300- and 850-ms basic cycle length (BCL). Effective refractory periods (ERPs) were determined at baseline and after application of propafenone (2 mg/kg), dofetilide (30 microg/kg), or chromanol 293b (10 mg/kg) by the extrastimulus technique (BCL 300 and 850 ms). At baseline, activation patterns and ERPs were uniform in all muscle layers. Propafenone homogeneously decreased conduction velocity and moderately prolonged ERPs without any regional differences. Dofetilide and chromanol 293b did not affect the spread of activation. Dofetilide exhibited reverse use-dependent effects on ERP, still preserving transmural homogeneity of refractoriness. Chromanol 293b led to a regionally uniform but more pronounced increase in local ERPs at faster than at slower pacing rates. CONCLUSIONS: At the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.

Multisite pacing for prevention of atrial tachyarrhythmias: potential mechanisms.

OBJECTIVES: To determine the effects of single-, dual-, triple- and quadruple-site atrial pacing on atrial activation and refractoriness in normal canine hearts. BACKGROUND: Multisite pacing has been suggested to be superior to single-site pacing for prevention of atrial tachyarrhythmias. However, the underlying electrophysiological mechanisms are undetermined at the moment, as is the rationale for the selection of pacing locations and the number of pacing sites. METHODS: In 13 normal beagle dogs, an epicardial multielectrode (128 bipoles) and a multiplexer mapping system were used to reconstruct epicardial atrial activation patterns obtained during simultaneous stimulation from up to four electrodes located in the high and low right and left atrium, respectively. For all pacing modes (single-, dual-, triple- and quadruple-site pacing), total activation times and local effective refractory periods at eight randomly selected sites as well as local recovery intervals were determined. In a subgroup of five dogs, total epicardial activation times were also obtained during single-site septal stimulation (septal group). RESULTS: Activation times and local recovery intervals were minimized by triple-site stimulation, whereas a fourth site did not produce further shortening. Septal stimulation produced epicardial activation times comparable to quadruple-site stimulation. Local refractory periods and their dispersion always remained unaffected. Functional conduction blocks apparent during single-site were found to resolve during multisite stimulation. CONCLUSIONS: Multisite pacing can prevent functional conduction blocks by multidirectional excitation and a reduction in total activation time. Triple-site and, possibly, septal pacing modes are expected to be most efficient because both minimize total activation times and maximize the multidirectionality of excitation. In spite of unaffected local refractory periods, the shortening of local recovery intervals might homogenize atrial repolarization and, thus, contribute to the preventive effects of multisite pacing.

Ventricular arrhythmias induced by endothelin-1 or by acute ischemia: a comparative analysis using three-dimensional mapping.

OBJECTIVES: To analyze three-dimensional activation patterns of ventricular arrhythmias induced by endothelin-1 in comparison with ischemia-induced tachycardias. METHODS: Following AV node ablation, sixty pin electrodes containing four bipoles each were inserted into both ventricles of ten foxhounds. Using a computerized mapping system, this would allow to simultaneously record 240 endo-, epi- and midmyocardial electrograms for reconstruction of the three-dimensional activation pattern. In five dogs, endothelin-1 was infused into the LAD at 60 pmol/min. In another five animals, the LAD was ligated. During the following 40 min, all ventricular arrhythmias were recorded for subsequent analysis. Furthermore, left ventricular conduction times during constant pacing and local effective refractory periods at eight left ventricular sites were determined before and after either intervention. RESULTS: Endothelin-1 had no significant effect on conduction time and refractoriness, whereas ligation prolonged both parameters significantly. Endothelin-1 as well as ligation induced multiple mono- and polymorphic nonsustained ventricular tachycardias. Endothelin-1-induced arrhythmias were exclusively based on focal mechanisms, whereas during ligation, macroreentrant mechanisms were involved in the maintenance of tachycardias in 29% of episodes. CONCLUSION: The differences in the effects of endothelin-1 and LAD ligation on electrophysiologic properties and the difference in the mechanism of induced ventricular tachycardias support the hypothesis that, apart from vasoconstrictive properties, endothelin-1 exerts an intrinsic arrhythmogenic effect.

[How to approach the patient with supraventricular tachycardia in the EP lab: A systematic overview]. / Diagnostik bei supraventrikulären Tachykardien : Wie ist das Vorgehen im elektrophysiologischen Labor?

The term supraventricular tachycardia (SVT) summarizes those tachycardias involving the atrial myocardium along with the atrioventricular (AV) node. The prevalence is about 2.25 per 1000 (without atrial fibrillation and atrial flutter) and, therefore, SVT represents one of the most common group of arrhythmias besides atrial fibrillation encountered in the emergency department especially since they tend to recur until definite therapy. The clinical symptoms may include palpitations, anxiety, presyncope, angina, and dyspnea. Pharmacological therapy of these arrhythmias often fails. The present article deals with the differential diagnosis of SVT and also introduces a series of manuscripts that provide detailed insight into the differential diagnosis and treatment of these arrhythmias.

The bone-implant interface of femoral stems with non-circumferential porous coating.

UNLABELLED: A histological study was performed of the bone-implant interface of fifteen titanium-alloy femoral stems with porous coating limited to three proximal areas that did not cover the full circumference of the device. The specimens were obtained at autopsy from ten cadavera at a mean of forty-six months (range, one to eighty-nine months) after the implant had been inserted without acrylic cement. The volume fraction of bone within the porous spaces (the percentage of the porous space that was filled with bone) and the extent of bone ingrowth (the percentage of the porous-coated surface covered with in-grown bone that was more than one-half fiber-diameter deep, as measured from the outer surface of the porous coating), were determined with histomorphometric methods. Eleven of the fifteen stems had bone within the porous coating that was in continuity with the surrounding medullary bone. The mean volume fraction of bone ingrowth in these specimens was 26.9 per cent (range, 12.2 to 61.0 per cent), and the mean extent of bone ingrowth was 64.3 per cent (range, 28.6 to 95.2 per cent). Both of these parameters increased with time. In the other four stems, the bone lacked continuity with the surrounding trabecular bed. Two of these stems had a limited amount of bone within the porous coating, and two stems (from one patient) had no bone ingrowth. Periprosthetic membranes surrounded by a shell of trabecular bone covered the uncoated surfaces of the stems. The membranes of implants that had been in situ for eight months or more demonstrated polyethylene wear debris, and other particles generated at the level of the joint, within histiocytes throughout the length of the femoral stem. CLINICAL RELEVANCE: The findings in this study are relevant to the utilization and mechanisms of failure of femoral stems inserted without cement. Bone ingrowth and the resulting stability of the implant can be achieved with porous-coated stems. However, the extent of the surface that is porous-coated must be sufficient to prevent trabecular fracture as a secondary mechanism of loosening. Interruptions in the circumferential extent of the porous surface are associated with the formation of periprosthetic membranes, which provide a pathway for migration of particulate wear and corrosion products to the distal part of the stem. A circumferential coating may retard the access of particles and thus decrease the possibility of diaphyseal osteolysis.

[Is the determination of the defibrillation threshold in patients with an implantable cardioverter-defibrillator still required?]. / Wird die Bestimmung der Defibrillationsschwelle bei Patienten mit implantierbarem Kardioverter/Defibrillator noch benötigt?

BACKGROUND: Intraoperative testing of implantable cardioverter-defibrillators (ICDs) is time consuming and associated with risks. In the present study, we elucidated whether the initial implantation of an ICD with high energy output makes intraoperative defibrillation threshold testing (DFTT) unnecessary even though antiarrhythmic (AA) therapy is needed in the future. METHODS: A total of 111 patients (94 men, 17 women) receiving an ICD with subsequent AA therapy (mexiletine, amiodarone, sotalol, flecainide) were analyzed retrospectively. DFT was performed during ICD implantation and after AA drug therapy. In a second step, DFT results from the study cohort were analyzed for implantation of virtual ICDs with either low (≤ 30 J, LOD), intermediate (34 J, IOD), or high energy output (36 J, HOD). RESULTS: In the study cohort, all patients reached the safety margin (SM) of 10 J between DFT and maximal shock energy of the ICD. After loading of AA agents, 6 patients (12%) with a LOD, 3 patients (11%) with an IOD, and 3 (13%) patients with a HOD failed the 10 J SM. Using virtual ICDs, 6 (5.5%) patients with a LOD, 1 patient (1%) with an IOD, and no patients with a HOD would have failed the 10 J SM. After loading of AA agents, 18 patients (16%) with a virtual LOD, 12 patients (10.8%) with an IOD, and still 9 patients (8%) with a HOD would have failed the 10 J SM. CONCLUSION: Our results demonstrate that the 10 J SM would have been achieved intraoperatively in all patients with virtual HOD ICDs. Thus, determination of the DFT during implantation does not seem to be obligatory. However, in patients receiving AA agents, DFT testing is still required.

Measurement of the 60Fe(n, gamma)61Fe Cross Section at Stellar Temperatures.

Observations of galactic gamma-ray activity have challenged the current understanding of nucleosynthesis in massive stars. Recent measurements of (60)Fe abundances relative to ;{26}Al;{g} have underscored the need for accurate nuclear information concerning the stellar production of (60)Fe. In light of this motivation, a first measurement of the stellar (60)Fe(n, gamma)(61)Fe cross section, the predominant destruction mechanism of (60)Fe, has been performed by activation at the Karlsruhe Van de Graaff accelerator. Results show a Maxwellian averaged cross section at kT = 25 keV of 9.9 +/-_{1.4(stat)};{2.8(syst)}mbarn, a significant reduction in uncertainty with respect to existing theoretical discrepancies. This result will serve to significantly constrain models of (60)Fe nucleosynthesis in massive stars.

Indications for predismissal testing with arrhythmia-induction in patients receiving an implantable cardioverter defibrillator.

UNLABELLED: Arrhythmia induction during implantation of cardioverter defibrillators (ICD) is a standard procedure. However, controversy exists regarding the need for routine arrhythmia induction before discharge from hospital (pre-hospital discharge (PHD) test). In order to reduce the number of tests we identified risk factors that predict relevant ICD malfunction. METHODS AND RESULTS: 965 patients receiving a first device implantation (n=724) or device/system replacement (n=241) between 1998 and 2004 were analysed. During implantation 176 (18%) complications (intraoperative undersensing of induced arrhythmias, unsuccessful arrhythmia-therapy or low DFT safety margin) occurred. Frequent (>4 times) intraoperative lead repositioning due to low sensing values was present in 44 patients (5%). 9% of the patients with first ICD implantation, 21% with device replacement and 27% with system replacement developed complications during PHD testing with arrhythmia induction. Intraoperative complications, although corrected during implantation, were independent risk factors for malfunction during PHD testing (p<0.05). Additional predictors for malfunction were intraoperative lead repositioning (>4 times) and a history of both VF and VT (p<0.05). Patients without intraoperative complications rarely developed malfunction during PHD testing (3.7% first device, 6.25% system replacement). Only in patients undergoing device replacement was a higher risk for failure (13%) evident. No risk factors could be identified for these subgroups. CONCLUSION: Routine arrhythmia induction during PHD is recommended in ICD patients with intraoperative complications, although corrected during implantation, as well as frequent intraoperatives lead repositioning. Patients undergoing device/system replacement uncomplicated implantation are not generally at low risk for device failure.

Regional differences in the dynamics of refractoriness in intact and hypertrophied in situ canine hearts.

OBJECTIVES: Functional re-entry is thought to represent the predominant mechanism underlying ventricular arrhythmias. Functional conduction block may be caused by regional dispersion of refractoriness (ERP). Dispersion of ERP may not be evident at baseline, but may occur with sudden changes in heart rate, as ventricular arrhythmias are commonly induced by short-long-short cycles. METHODS: We examined the dynamics of local ERPs at two left ventricular (LV) sites in dogs with either no structural heart disease or biventricular hypertrophy (BVH). ERPs were determined at each of four bipoles of two adjacent needle electrodes in the LV apex and the lateral wall. The stimulation protocol included two different basic cycle lengths, one or two longer cycles after a train of 6 or 5 shorter cycles, and one shorter cycle after a train of 6 longer cycles. RESULTS: In normal dogs, a significant apicolateral ERP gradient was only evident with the longer basic cycle length. One shorter cycle was sufficient to dissolve that gradient. One longer cycle was enough to create a regional ERP gradient. Dynamic regional gradients occurred because the apex responded more markedly and more readily to abrupt changes in cycle length. BVH led to an increase in ERP at both LV sites and to an aggravation of regional ERP gradients. CONCLUSIONS: Dynamic ERP behavior seems to depend on topography and underlying pathology. Abrupt changes in heart rate might induce dynamic refractory gradients between various regions of the normal heart, but also between adjacent regions inhomogenously affected by hypertrophy.

[Micturition and urinary tract infection in girls. 4. Various aspects of age factors]. / Miktionsverhalten und Harntraktinfektion bei Mädchen. 4. Mitteilung: Einige Aspekte der Altersabhängigkeit.

First affection with urinary tract infection, relapses, and micturition pattern were analyzed depending on age. It is demonstrated that the decreased UTI rate after the 12th year rather depends on the micturition habit than on puberty.

[Micturition retention and urinary tract infection in girls. Detection of functional micturition disorders with special reference to anamnesis]. / Miktionsverhalten und Harntraktinfektion bei Mädchen. 5. Mitteilung: Die Erfassung funktioneller Miktionsstörungen unter besonderer Berücksichtigung der Anamnese.

The normalization of functional micturition disturbances obtains an increasing importance in the treatment and guidance of girls with urinary tract infections. Our experience in the detection of an abnormal micturition pattern is reported. A detailed interrogation of the parents feasible in any outpatient practice is more emphasized than investigations by means of technical devices.

[Urination habits and urinary tract infections in girls. 3. Dependency of therapy results from length of therapy and from urination habits]. / Miktionsverhalten und Harntraktinfektion bei Mädchen. 3. Mitteilung: Die Abhängigkeit des Therapieerfolges von der Therapiedauer und vom Miktionsverhalten.

Urinary tract infections in girls are promoted by abnormal micturition habit. Aside from applying antibiotics, the training of voiding discipline is very important for UTI prevention. The duration of medicamentous prevention should pay regard to the behaviour of micturition.

[Micturition behavior and urinary tract infection in girls. 2. Reduction in incidence of recurrence following normalization of micturition behavior]. / Miktionsverhalten und Harntraktinfektion bei Mädchen. 2. Mitteilung: Der Rückgang der Rezidivfrequenz nach Normalisierung des Miktionsverhaltens.

Relapse rate of urinary tract infection in girls with functional micturition disturbances by far exceeds that under normal micturition habits. When the habit of micturition can be normalized or at least considerably improved the relapse rate is distinctly lowered, a causal nexus thus can not be doubted.