Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines.

Imatinib mesylate is a selective inhibitor of the oncogenic tyrosine kinase, Bcr-Abl, and is widely used as a first-line treatment for chronic myeloid leukaemia (CML). Prolonged monotherapy is frequently associated with patients becoming refractory to imatinib. Therefore, there is considerable interest in small molecule inhibitors which may be used either as replacements or as adjuncts to existing imatinib therapy. For this purpose, it is most likely that drugs which do not share imatinib's mechanism of action will be most valuable. We compared two such compounds with different modes of action, adaphostin and 17-allylamino-17-demethoxygeldanamycin (17-AAG), for their cytotoxic effect and ability to induce the downregulation of cellular proteins in a murine haemopoietic cell line transformed with human p210(Bcr-Abl), and two subclones resistant to imatinib owing to an Abl-kinase domain mutation (E255K) or amplification of the BCR-ABL gene, respectively. We found that, whereas 17-AAG selectively killed Bcr-Abl-positive cells and inhibited proteins dependent on heat-shock protein 90 for their stability (p210(Bcr-Abl) and Akt), adaphostin induced the downregulation of multiple cell-signalling proteins (p210(Bcr-Abl), Akt, Bcr, Abl and STAT5a) and was cytotoxic to both Bcr-Abl-positive and -negative cells. We suggest that both compounds may prove useful in the treatment of CML but caution that undesirable side-effects may result from the inhibition of multiple cell signalling proteins.

[Experience with surgical treatment of prosthetic valve endocarditis]. / Múbillentyú-endocarditis sebészi kezelésével szerzett tapasztalataink.

Prosthetic valve endocarditis (PVE) is a rare but dangerous complication that may occur after the implantation. The authors retrospectively summarize their 11-year experience in treating PVE. 2357 prosthetic valve (PV) implantations were performed over 11 years at the Department of Cardiovascular Surgery, Semmelweis University, Budapest, PVE was found to be the indication for operation in 1.8% of the cases (43/2357). 43 surgical interventions were carried out on 38 patients (mean age: 52.5 yrs, male/female ratio: 25/13). Blood cultures were positive in 86% and negative in 14% of the cases. The infected PV-s were replaced emergently (14%), urgently (79%) or electively (7%). The explanted valves were aortic in 55% and mitral 45% of the cases, 63% were mechanical and 37% biological. PVE followed the primary PV implantation in less than a year in 39.5%. Infected environment during the primary PV implantation was found to be a predisposing factor for the late endocarditis episodes. The mean age of the infected and explanted aortic bioprosthetic valves was significantly higher than that of explanted mechanical valves (p < 0.05). No such difference could be found at the mitral valves. The explanted valves were replaced by mechanical (75.5%) or biological (22.5%) devices. Homograft was implanted once. Early postoperative mortality of the primary PV replacements was 10.5%) devices. Homograft was implanted once. Early postoperative mortality of the primary PV replacements was 10.5%. Endocarditis reoccurred in 20% of the cases. Means follow-up duration was 45.5 months. Two-, five- an 10-year survival were 75%, 64% and 51% respectively. In conclusion in the surgical treatment of PVE, bioprosthetic and mechanical valves are suitable alternatives as opposed to homografts and freestyle stentless valves.

[Biventicular pacing in patients with severe heart failure]. / Súlyos szívelégtelenség kezelése biventricularis ingerléssel.

According to initial clinical results biventricular pacing seems to be effective in the treatment of patients suffering from drug refractory severe heart failure combined with intraventricular conduction disturbance. Biventricular cardioverter defibrillators and biventricular pacemakers were implanted in patients suffering from drug refractory severe heart failure in 3 and in 2 cases, respectively (follow up > 6 months). NYHA III-IV functional class, low left ventricular ejection fraction (23.2 +/- 5.4%), wide QRS (> 150 ms) with left bundle branch block and lateral dyssynchrony were present in each case. The left ventricle was enlarged in each patient (end-diastolic/end-systolic diameter: 78.6 +/- 9.2/66.2 +/- 8.1 mm). The indications of cardioverter defibrillator implantations were both sustained ventricular tachycardia and ventricular fibrillation, nonsustained ventricular tachycardia combined with syncope in 2 and in 1 case, respectively. The duration of QRS decreased (190 +/- 36 vs. 134 +/- 17 ms, p = 0.012) and wall movement disorder disappeared. At the last follow up every patients were in NYHA II functional class and a decrease in left ventricular diameter could be observed (end-diastolic: 72 +/- 10.4 mm, p = 0.07; end-systolic: 62 +/- 10 mm, p = 0.09). During the follow up period (7.3 +/- 1.7 months) 18 episodes of ventricular arrhythmias could be detected in the same patient. Biventricular pacemakers and cardioverter defibrillators were implanted and applied successfully in the treatment of congestive heart failure for the first time in Hungary. The effect of biventricular pacing on morbidity and mortality, the cost-effectiveness, the exact indication and the combined use with cardioverter defibrillator have yet to be proven in future randomized trials.

[Simultaneous carotid and coronary operations: experience and results of 11 years (1990-2000)]. / Szimultán végzett carotis-coronaria mútétek: 11 év tapasztalatai és eredményei (1990-2000).

Between 1990-2000 163 coronary + carotid procedures were performed. The mean age was 4 years higher than it was at patients underwent isolated CABG (63.4 y vs 59.8 y). Clinically proven obliterative artery diseases in other anatomical regions were also present in more than 60% of patients. The half of the procedures were performed under emergency and urgent circumstances. The cardiac status and the coronary morphology were found to be unstable in half of the patients. The "Euroscore" risk evaluation model was used for risk scoring. The mean score value was as high as 6.26. According to this the estimated surgical lethality could have been as high as 11.2%. The real surgical lethality value was far under this estimated level (7.36%). The 1, 5, 10 year survival rate were as high as 89%, 82%, 68% (Kaplan-Meier). The majority of the patients was in NYHA I-II at the end of the follow-up period. The majority of the early and late deaths were found to be myocardial in origin. The estimated surgical risk of the simultaneous procedures could be reduce by accepting of the severe surgical indications existing at this surgical field and with the availability of an experienced operating team.

[Coronary artery bypass grafting without extracorporeal circulation]. / Koszorúérmútétek extrakorporális keringés alkalmazása nélkül.

At the Department of Cardiovascular Surgery of Semmelweis University, Budapest we have performed 57 coronary bypass operations without using cardiopulmonary bypass between 1996 and September 2001. Due to the learning phase we preferred cases of 1-2 wessel diseases, and revascularisation necessary on the anterior surface of the heart. In the beginning the stabilization of the operative field was ensured by manual methods, then by applying mechanical stabilization devices (Octopus 2, Genzyme). As to the type of operative indication overwhelmingly elective operations were performed. REDO procedure, i.e. repeated coronary bypass operation was carried out in 2 cases. Forty-eight patients recovered without complication. Two patients died, one of them suffered perioperative infarction, the other died due to cerebral complication. Total mortality was 3.5%. As a consequence of cardiac ischaemia in the direct postoperative period, we performed emergent coronary ballon dilatation (PTCA) in two cases. In three cases we experienced perioperative infarction. We followed up our patients by way of interview and telephone interview. The follow-up is 95%, the average follow-up time is 15 months. Significant cardiac event (infarction, PTCA or REDO coronary operation) took place in the case of 7 patients. In the majority of our patients the operation resulted in an improvement of condition, 43 patients are free from angina.

[Multichamber pacing--a new non-pharmacologic method for the treatment of severe heart failure]. / Többüregú ingerlés--a súlyos szívelégtelenség kezelésének új nonfarmakológiás módszere.

According to initial clinical results biventricular pacing seems to be effective in the treatment of patients suffering from drug refractory severe heart failure combined with intraventricular conduction disturbance. Biventricular cardioverter defibrillators and biventricular pacemakers were implanted in patients suffering from drug refractory severe heart failure in 10 and in 15 cases, respectively. NYHA III-IV functional class, low left ventricular ejection fraction (24.2 +/- 6%), wide QRS (> 150 ms) with left bundle branch block and lateral dyssynchrony were present in each case. The left ventricle was enlarged in each patient (endodiastolic/endsystolic diameter: 78.6 +/- 9.2/68.2 +/- 8.3). The indications of cardioverter defibrillator implantations were both sustained ventricular tachycardia and ventricular fibrillation, nonsustained ventricular tachycardia combined with syncope in 7 and in 3 case, respectively. The duration of QRS decreased (187 +/- 32 vs. 136 +/- 19 ms, p = 0.012) and wall movement disorder disappeared. At the last follow up every patients were in NYHA II functional class and a decrease in left ventricular diameter could be observed (endodiastolic: 70.3 +/- 9.1 mm, p = 0.04; endosystolic: 61.9 +/- 8.8 mm, p = 0.04). During the follow up period (8.8 +/- 5.1 months) 18 episodes of ventricular arrhythmias were detected in the same patient, 2 patients died (1 arrhythmia death, 1 sudden cardiac death). Biventricular pacemakers and cardioverter defibrillators were implanted and applied successfully in the treatment of congestive heart failure for the first time in Hungary.

[Atrial fibrillation after open-heart surgery--incidence, prevention and treatment]. / Posztoperatív pitvarfibrillàció okai, gyakorisága, megelözése és kezelése szívsebészeti betegeknél.

Atrial fibrillation is a common problem in the postoperative period following open-heart surgery. The pathogenesis of postoperative atrial fibrillation is likely to be multifactorial, however increased sympathetic activation may play a significant role. The aim of the study was to detect the incidence and possible reasons of atrial fibrillation in the first three postoperative days after open-heart surgery. Atrial fibrillation was detected in a total of 48 patients (mean age 64.8 +/- 8.8 years) of the 302 consecutive patients included in the study. The incidence of atrial fibrillation was 15.9%. In the history of patients with atrial fibrillation paroxysmal or persistent atrial fibrillation occurred in 18 cases. Acute ischaemia, hypopotassemia, high dose catecholamines contributed to the development of arrhythmias in 6, 4 and 4 cases, respectively. Lack of perioperative beta-blocker treatment was seen in 35 cases. Postoperative bleeding and reoperation occurred prior to the onset of atrial fibrillation in 9 instances. The applied antiarrhythmic therapy was metoprolol, amiodarone, propafenon and electrical cardioversion in 33, 21, 4 and 2 cases, respectively. Incidence of atrial fibrillation was found significantly lower in patients receiving beta-blocker premedication (13/181 [7.18%] versus 35/121 [28.9%]). There was no correlation between the incidence of atrial fibrillation and the length of the surgery, aortic-cross clamp time and the number of bypass grafts. Absence of preoperative beta-blocker treatment, previous atrial fibrillation and combined surgery were found to be strong predictors of atrial fibrillation. There was weaker association with increased age. On the basis of the outcome of our study beta-blocker premedication is suggested in most patients undergoing open-heart surgery.

[Traumatic rupture of the descending aorta]. / Az aorta descendens traumás eredetü rupturája.

During a ten-year period 16 patients were seen with aortic rupture and false aneurysm secondary to blunt trauma. One patient underwent an acute operation, 4 patients had operative therapy elective delayed and 11 patients were operated on for chronic traumatic false aneurysm. Operative delay was done in case of simultaneous multisystem injury (e.g. shock caused by abdominal injuries, cerebral contusion or pulmonary contusion on the right side). The shunt bypass method of repair was used in the case of 3 patients, cardiopulmonary bypass in 6 cases and simple aortic cross-clamping in 6 patients. One operation was performed without aortic cross-clamping. Primary repair was achieved in three patient, in 3 more cases a patch was inserted and in 9 cases interposition Dacron grafting was accomplished. One "wrapping" operation was performed. In 2 cases, reoperation was necessary because of postoperative bleeding. One patient died in the perioperative period. Right sided hemiparesis occurred in one patient postoperatively. Rupture does not affect the whole aortic wall, especially in young people because of the natural elasticity of vessel. The appearing shock and hypotension might protect the mediastinal pleura against bursting. This could provide a chance to survive. Our experience indicate: Elective delay of operation in patients with multiple system injuries can be achieved with antihypertensive therapy.

[Simultaneous occurrence and treatment of right atrial myxoma and extensive colonic polyposis causing recurrent intestinal hemorrhages]. / Jobb pitvari myxoma és kiterjedt--ismételten vérzést okozó--vastagbél-polyposis együttes elöfordulása és kezelése.

The authors describe the case history of 68 year old man. Right atrial myxoma had been diagnosed two years prior to this present observation, however surgical intervention has been contraindicated due to high operative risk. Later the patient was referred to a cardiological evaluation because of chronic atrial fibrillation before a cataract surgery in a symptom free condition. The right atrial myxoma caused inflow obstruction and tricuspid regurgitation was removed before the eye surgery. In addition, tricuspid valve replacement and revascularization of three coronary arteries has been performed. The patient receiving chronic anticoagulant therapy experienced severe gastrointestinal bleeding the source of which turned out to be a partially malignant colon polyposis. The polyps were successfully removed by coloscopy and intra operative coloscopy. No gastrointestinal bleeding has been observed afterwards in spite of the continued anticoagulation. After review of the literature the authors observed that according to their knowledge the common occurrence of the right atrial myxoma and the colon polyposis had not been described before.

[Coronary surgery at the Cardiovascular Surgical Clinic (1976-1990)]. / Coronariasebészet az Er- és Szívsebészeti Klinikán (1976-1990).

In the Cardiovascular Surgical Clinic of the Semmelweis Medical University of Budapest the first coronary artery bypass grafting (CABG) procedure was performed in 1975. Since that time coronary artery surgery has become a routine everyday practice representing more than half of the total workload of adult cardiac surgery. The analysis of 1347 operations performed between 1976-1990 on patients with coronary heart disease showed the followings: the first few years--so called learning curve of CABG operations is characterised by high mortality. With passing time the number of cases performed each year increased rapidly and the surgical technique has improved too. At the same time the operative mortality figures showed decreasing tendency--it was 2.1% for the last 609 cases. All observed parameters showed some progress: in 1990 the average number of grafts per patient was 3.09, internal mammary artery usage 15 percent and the mean aortic cross clamp time per anastomosis 24.5 minutes. Complete myocardial revascularisation is the key point of coronary artery surgery. In order to achieve this target in all operated cases further technical improvement is necessary.

[Development and results of valve replacement surgery at the Városmajor Clinic 1976-1990 (retorospective clinical analysis)]. / A szívbillentyü-sebészet fejlödése és eredményei a Városmajori Klinikán 1976-1990 (retrospektív klinikai analízis).

In Hungary valve replacement is still a major indication for heart surgery in adults. In the Cardiovascular Surgical Clinic of Semmelweis Medical University of Budapest from 1976 to 1990 2435 patients were operated for valve disease. Majority of the cases had single (aortic n = 856, mitral n = 912) or double (aortic + mitral n = 513) valve replacement. Over this 15 years period there have been many alterations in patients characteristics and surgical technique as well. In spite of the increasing mean age of patients the operative mortality has decreased (in the last 5 years period it was 2.7%, 5.5% and 7.9% in the three groups respectively). At the same time the number of patients requiring valve re-replacement or combined valve + coronary procedure has increased. The use of bioprosthetic valves has fallen below 10 percent from the 60--80 percent observed between 1976--1980. The analysis showes excellent surgical results in the field of valve replacement in Hungary.

Biological valve prosthesis replacement--experiences and considerations.

Between 1976 and 1991. 1.017 tissue valve prostheses were implanted in 801 patients. During the same period 1876 mechanical valve prostheses were replaced. The hospital mortality was 8.1%. Till 1991 230 bioprostheses (22.6%) in the case of 166 patients (20.7%) had to be removed and replaced by other valve prostheses. There are no significant differences concerning the mortality between the first (8.1%) and the second operations (9.1%), and the durability of the various types of bioprostheses used, however, calcification, degeneration and other complications occurred more frequently and earlier in the case of mitral (24.5%) than in aortic (18.9%) bioprostheses, and in younger patients than in the older ones, as well. The mean age of patients was 46 years at the time of the first and 49 years at the time of the second operation. The incidence of reoperations was the highest in the seventh year after the first surgical intervention. In general, one size smaller prostheses were used in valve replacements after the removal of the first bioprostheses.

Pacemaker twiddler's syndrome (rotation of the pacemaker around the electrode cable, a rare complication of pacemaker therapy).

Rotation of the pacemaker generator around the electrode cable (i.e. twiddler's syndrome) was observed by the authors in six cases during the implantation of 4250 pacemakers. Twiddler's syndrome developed in three cases following implantation and in three cases after the replacement of the pacemaker. As a result of the rotation of the device, displacement of the electrode occurred in all cases. The factors predisposing to rotation of the device were as follows: (i) a loose, dilated pocket in 5 cases; (ii) seroma formation around the device in 2 cases; (iii) manipulation with the pacemaker in one case. For treating twiddler's syndrome, reimplantation was performed, fashioning a small and tight pocket for the device and fixing it by transfixing sutures. After reimplantation, the patients became complaint free, no recurrences occurred.

Enzymatic hydrolysis of electrically charged substrates.

A study has been made on the hydrolytic action of porcine kidney aminoacylase I (EC 3.5.1.14.) upon electrically charged substrates containing ionic groups both in the acyl moiety and in the C-terminal amino acids. In all cases a decrease in reactivity was found. An attempt has been made to elucidate the nature of this action.

The electrophysiological peculiarities of childhood tachyarrhythmias.

Electrophysiological analysis of 20 patients in child or adolescent age affected by paroxysmal tachycardia has been performed. In 16 cases the tachycardia was supraventricular and in 4 cases it was ventricular. Evaluation of the electrophysiological parameters revealed certain characteristics of childhood tachyarrhythmias, viz. (1) adequate sinus node function, absence of sinus dysfunction, (2) absence of brachycardia, (3) acceleration of anterograde and retrograde atrioventricular impulse conduction systems.

Clinical and experimental study of cold cardioplegic myocardial protection.

The authors used a multi-dimensional approach to the study of the effects of intra-operative myocardial protection; the results of three series of investigations are reported. First, conditions underlying the effectiveness of the authors' modified cardioplegic solution were studied by laboratory and histological methods in ex vivo guinea pig hearts. Evidence is presented for the detrimental effects of catecholamines and the beneficial action of inosine. The second part of the report deals with problems of effective myocardial cooling in partially ischaemic canine hearts, investigated by infrared thermographic examinations of temporal and spatial thermal distribution over the entire visible cardiac surface. At last the authors present the result of their complex intra- and postoperative enzyme analysis combined with mathematical evaluation (cluster analysis in a group of patients suffering from ischaemic heart disease).