Search

Treatment results of AML in elderly patients are unsatisfactory. In an open label randomized phase II study, we investigated whether addition of the XPO1 inhibitor selinexor to intensive chemotherapy would improve outcome in this population. 102 AML patients > 65 years of age (median 69 (65–80)) were randomly assigned to standard chemotherapy (3 + 7) with or without oral selinexor 60 mg twice weekly (both arms n= 51), days 1–24. In the second cycle, cytarabine 1000 mg/m2twice daily, days 1–6 with or without selinexor was given. CR/CRi rates were significantly higher in the control arm than in the investigational arm (80% (95% C.I. 69–91%) vs. 59% (45–72%; p= 0.018), respectively). At 18 months, event-free survival was 45% for the control arm versus 26% for the investigational arm (Cox-p = 0.012) and overall survival 58% vs. 33%, respectively (p= 0.009). AML and infectious complications accounted for an increased death rate in the investigational arm. Irrespective of treatment, MRD status after two cycles appeared to be correlated with survival. We conclude that the addition of selinexor to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients. (Netherlands Trial Registry number NL5748 (NTR5902), www.trialregister.nl).

More effective treatment modalities are urgently needed in patients with acute myeloid leukemia (AML) of older age. We hypothesized that adding lenalidomide to intensive standard chemotherapy might improve their outcome. After establishing a safe lenalidomide, dose elderly patients with AML were randomly assigned in this randomized Phase 2 study (n?=?222) to receive standard chemotherapy (“3?+?7”) with or without lenalidomide at a dose of 20?mg/day 1–21. In the second cycle, patients received cytarabine 1000?mg/m2twice daily on days 1–6 with or without lenalidomide (20?mg/day 1–21). The CR/CRi rates in the two arms were not different (69 vs. 66%). Event-free survival (EFS) at 36 months was 19% for the standard arm versus 21% for the lenalidomide arm and overall survival (OS) 35% vs. 30%, respectively. The frequencies and grade of adverse events were not significantly different between the treatment arms. Cardiovascular toxicities were rare and equally distributed between the arms. The results of the present study show that the addition of lenalidomide to standard remission induction chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR2294 in The NederlandsTrial Register (www.trialregister.nl).

Introduction: Increasing attention is being given to the roles of data management and data sharing in the advancement of research. This study was undertaken to explore opinions and past experiences of established dental researchers as related to data sharing and data management.Methods: Researchers were recruited from the International Association for Dental Research scientific groups to complete a survey consisting of Likert-type, multiple-choice, and open-ended questions.Results: All 42 respondents indicated that data sharing should be promoted and facilitated, but many indicated reservations or concerns about the proper use of data and the protection of research subjects. Many had used data from data repositories and received requests for data originating from their studies. Opinions varied regarding restrictions such as requirements to share data and the time limits of investigator rights to keep data. Respondents also varied in their methods of data management and storage, with younger respondents and those with higher direct costs of their research tending to use dedicated experts to manage their data.Discussion: The expressed respondent support for research data sharing, with the noted concerns, complements the idea of developing managed data clearinghouses capable of promoting, managing, and overseeing the data-sharing process.Knowledge Transfer Statement: Researchers can use the results of this study to evaluate and improve management and sharing of research data. By encouraging and facilitating the data-sharing process, research can advance more efficiently, and research findings can be implemented into practice more rapidly to improve patient care and the overall oral health of populations.

Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1without FLT3-ITD (71±4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23±8% and 12±6%, respectively. Patients with wild-type NPM1without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23±4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.

Atrial fibrillation is the most frequent arrhythmia the cardiologist is confronted with. Since most patients suffer under the tachyarrhythmic disturbance, immediate treatment of the arrhythmia is mandatory. Given the expertise of the therapist and the opportunity of monitoring for several hours as well as of innediate DC cardioversion, outpatient initiation of medical arrhythmic treatment is possible in selected patients. Amiodaron in the antiarrhythmic agent which can be considered as safe under these conditions, even in patients with structural heart disease. The class 1C agents flecainite and propafenone are restricted for patients with idiopathic atrial fibrillation. Taking into consideration the structural heart disease and the selection of the specific antiarrhythmic agent, medical antiarrhythmic therapy can be considered as safe in the ambulatory setting. Vorhofflimmern ist die häufigste Arrhythmie in der Praxis des Internisten und Kardiologen. Die Patienten sind meist so beeinträchtigt, dass eine unmittelbare Behandlung geboten ist. Unter der Voraussetzung der umfassenden Erfahrung des Therapeuten mit der Arrhythmie und der Möglichkeit einer Rhythmusüberwachung für einige Stunden sowie der DC-Kardioversion im Notfall ist die Therapieeinleitung im ambulanten Bereich möglich. Als sicherste Substanz ist hierbei Amiodaron anzusehen, das auch für kompensierte Patienten mit struktureller Herzkrankheit in Frage kommt. Die Klasse 1C-Substanzen, Propafenon oder Flecainid, sind Patienten mit idiopathischem Vorhofflimmern vorbehalten. Unter Berücksichtigung der Grundkrankheit und bei entsprechender Auswahl des Antiarrhythmikums kann die Therapie von Vorhofflimmern auch unter ambulanten Bedingungen sicher und effektiv gestaltet werden.

The majority of cardioverter/defibrillator (ICD) implantations are currently performed with a non-thoracotomy approach. From November 1993 to January 1995, 46 patients underwent implantation of a PCD 7219C with an “active-can” lead configuration at our institution. While the chronic stability of the defibrillation threshold (DFT) for an epicardial lead system is well established, the results are still inconsistent for non-thoracotomy lead systems. Accordingly, the aim of the present study was to compare the acute and chronic defibrillation thresholds of the ICDs implanted with an “active-can” lead system in order to assess the chronic stability of these systems.¶ ??The defibrillation energy requirements were measured at implant, prior to hospital discharge, three, six and twelve months after implantation of the defibrillator. The patient group consisted of 8?females and 38 males with a mean age of 57.2 years. The mean left ventricular ejection fraction was 43.8%. The most frequent underlying heart disease was coronary artery disease in 31 of 46 patients. Eight patients had idiopathic dilated cardiomyopathy.¶ ??In 39 of 46 patients, the defibrillation threshold could be successfully determined at all 4 time points after implantation. The mean defibrillation energy requirement at the time of implantation was 9.2±5.9 Joules (J). The subsequent mean energy requirements were 7.6±4.8 J at pre-hospital discharge, 8.6±5.7 J at the 3 month, 8.1±6.0 J at the 6 month and 8.6±5.8 J at the 12 month follow-up visits. The mean defibrillation threshold was lowest at the time of prehospital discharge, significantly lower than at the time of initial implantion (p=0.021). However, at all later time points up to one year, there was no significant difference in the DFT as compared with the time of initial implantation. Comparing the DFT at the time of implantation and the DFT at all other time points, there were no significant differences (9.23 vs. 8.56 J, p=0.291). Although there was an initial decrease in the DFT at seven to ten days, the long-term stability of the DFT up to one year remained stable in the devices with the “active-can” lead system. Die Mehrzahl der Neuimplantationen aller Kardioverter-/Defibrillator-Systeme erfolgt heute ohne Thorakotomie mit endovenösen Elektrodensystemen. Für epikardiale Systeme wurde die Langzeitstabilität für die Defibrillationsschwelle (DFT) eingehend untersucht. Für den Verlauf der DFT bei transvenöser Implantationstechnik liegen bisher widerspüchliche Ergebnisse vor. Ziel der vorliegenden Untersuchung war es, die akute und chronische Defibrillationseffektivität bei Patienten mit implantierbarem Defibrillator und „Active-Can“-Elektrodenkonfiguration im Langzeitverlauf über 12 Monate zu vergleichen. Die bei Implantation des Defibrillators mit einem endokardialen Elektrodensystem erreichte Defibrillationseffektivität wurde postoperativ vor Entlassung aus der Klinik, nach 3, 6 und 12 Monaten erneut bestimmt. Das Patientenkollektiv bestand aus 8 Frauen und 38 Männern mit einem mittleren Alter von 57,2±13,2 (22–76) Jahren. Die mittlere linksventrikuläre Ejektionsfraktion betrug 43,8±16,9 (15–82)%. Der überwiegende Anteil der Patienten hatte eine koronare Herzerkrankung (67,4 %); acht Patienten hatten eine dilatative Kardiomyopathie.¶ ??Bei 39 Patienten wurde die DFT zu den geplanten fünf Testzeitpunkten bestimmt. Die mittlere DFT bei Implantation betrug 9,2±5,9 Joule (J), postoperativ vor Entlassung 7,6±4,8 J, bei der 3-Monats-Kontrolle 8,6±5,7 J, nach 6 Monaten 8,1±6,0 J und nach 12 Monaten 8,6±5,8 J. Die DFT vor Entlassung war signifikant niedriger als bei Implantation (7,6 J versus 9,2 J; p=0,021). Zwischen der DFT bei Implantation und der DFT bei der 3-Monats-Kontrolle und im weiteren Verlauf bestand kein signifikanter Unterschied (9,23 versus 8,56; p=0,291). In der Multivarianz-Analyse zeigte sich für die DFT eine zeitliche Abhängigkeit, die durch den signifikanten Abfall der DFT zum Zeitpunkt der Entlassung bedingt ist. Diese Verringerung der DFT hatte keinen Einfluss auf die Stabilität der Defibrillationsschwelle.¶ ??Bei ICDs mit einem „Active-Can“-Elektrodensystem erlaubt somit die intraoperativ bestimmte Defibrillationsschwelle eine gute Vorhersage der chronischen Defibrillationseffektivität.

Zusammenfassung: Die Möglichkeiten von Magnesium in der Notfallbehandlung anhaltender ventrikulärer Tachykardien werden dargestellt. Bei Patienten mit Torsade-de-pointes-Tachykardien, als deren Pathomechanismus frühe Nachpotentiale angenommen werden, konnte durch die Bolustherapie mit Magnesium die Unterbrechung und Suppression der tachyarrhythmischen Anfälle zuverlässig erreicht werden. Patienten mit monomorpher Tachykardie zeigten eigenen Untersuchungen zufolge nur in 20 bis 30% der Fälle unter dem Einfluß von 2×6 mmol bzw. 2×9 mmol Magnesium eine Beendigung der Rhythmusstörung. Die elektrophysiologischen Parameter wie RR-Intervall während der Tachykardie, Dauer und Form der monophasischen Aktionspotentiale sowie des QRS-Komplexes zeigten keine gerichtete Änderung und ließen keinen Rückschluß auf den Mechanismus der Magnesiumwirkung zu, so daß auch unspezifische Wirkungen wie die Aktivierung des autonomen Nervensystems als Einflußfaktoren möglich sind. Die Ergebnisse entsprechen im wesentlichen den Mitteilungen anderer Untersucher. Fazit: Die Möglichkeiten von Magnesium (i. v.) für die Notfallbehandlung monomorpher ventrikulärer Tachykardien bei struktureller Herzkrankheit sind begrenzt. Im Gegensatz hierzu kann die Magnesiuminjektion als Mittel der Wahl zur Unterbrechung und Suppression von Torsade-de-pointes-Tachykardien gelten.

The electrophysiologic effects of dextro (d)-and levo (l)-verapamil on sinoatrial (SA) and atrioventricular (AV) node function were studied in ten patients undergoing electrophysiologic evaluation of their supra-ventricular tachyarrhythmias. Both isomers elicited a significant prolongation of sinus node recovery time (SNRT) and AH interval. No difference between d- and l-verapamil regarding the magnitude of the effects, were observed. However, 50 mg d-verapamil was required to elicit the same electrophysiologic effects as 5 mg l-verapamil. The d- and l-verapamil plasma concentrations associated with the maximum effect on AH interval and SNRT showed a more than 20-fold difference (d: 380 ng/ml; l: 19 ng/ml). These data demonstrate that both verapamil isomers possess qualitatively similar slow channel blocking effects on the SA and AV node in humans, but the lisomer is 20 times more potent than the disomer.

Summary Chronic recurrent ventricular tachycardias represent potentially life-threatening cardiac arrhythmias. We used programmed ventricular stimulation for diagnosis, therapy and control of antiarrhythmic therapy in 17 patients with recurrent ventricular tachycardia. Ventricular tachycardia could be reproducibly induced in 15 patients by programmed stimulation, QRS morphology and rate being comparable to the spontaneously occurring tachycardia. Programmed stimulation was repeated under antiarrhythmic drug therapy. Over a follow-up period of 8 months (3–13 months), are results of the acute electrophysiologic study seem to be predicting oral long-term antiarrhythmic drug therapy. Application of programmed stimulation is associated with potential risks: induction of “non-clinical” more frequent tachycardia: 3/17 pat.=18%; acceleration of the rate of tachycardia while trying to interrupt it: 5/17 pat.=30%; necessity of DC-cardioversion: 6/17 pat.=35%. Despite these risks, programmed ventricular stimulation offers substantial improvement of diagnosis and control of therapy of severely symptomatic patients with suspected or documented ventricular tachycardia and/or fibrillation.

Summary: In 15 patients with recurrent ventricular tachycardia, the hemodynamic effects of amiodarone were evaluated under oral loading (1000 mg/day for 14–16 days) and during chronic treatment (600 mg/day for a further 10 weeks). In all patients, coronary artery disease was present with a mean ejection fraction of 37%±10%. The cardiac output during the sinus rhythm, as determined by thermodilution, did not change significantly during loading with amiodarone. During ventricular tachycardia, the cardiac output increased from 3.7 ±1. 3 to 4.5 ± 1.61/min under the influence of amiodarone in 5 patients. Echocardiographic measurements of the left ventricle dimensions did not show a directed change of the end-diastolic and endsystolic diameters and the fraction shortening at the end of the loading period and after 3 months of maintenance therapy. No negative inotropic effect of amiodarone could be demonstrated in patients with recurrent ventricular tachycardia and impaired left ventricular function due to coronary artery disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The alcohol (VI), an analogue of δ‐santalol (VII), is prepared by two ways, starting from isocamphenilanyl propionic acid (II) or from the easily accessible ketone (VIII).